{
 "cells": [
  {
   "cell_type": "markdown",
   "id": "c8a4fbd7",
   "metadata": {},
   "source": [
    "# Fine-tuning on Pre-trained Model for Cell-type Annotation\n",
    "In this tutorial, we demonstrate how to fine-tune a pre-trained model on a new dataset for the cell type annotation task. We use the Multiple Sclerosis dataset as an example and fine-tune on the pre-trained whole-body model. Please download the dataset folder from https://drive.google.com/drive/folders/1Qd42YNabzyr2pWt9xoY4cVMTAxsNBt4v?usp=sharing\n",
    "\n",
    "We summarize the fine-tuning pipeline in the following steps, which can be used as a general recipe for finetuning on cell-type annotation tasks and beyond: \n",
    "\n",
    "     1. Specify hyper-parameter setup for integration task\n",
    "     \n",
    "     2. Load and pre-process data\n",
    "     \n",
    "     3. Load the pre-trained scGPT model\n",
    "     \n",
    "     4. Finetune scGPT with task-specific objectives\n",
    "     \n",
    "     5. Evaluate fine-tuned scGPT"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "9406b4da",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "/root/anaconda3/envs/scgpt_new/lib/python3.10/site-packages/tqdm/auto.py:21: TqdmWarning: IProgress not found. Please update jupyter and ipywidgets. See https://ipywidgets.readthedocs.io/en/stable/user_install.html\n",
      "  from .autonotebook import tqdm as notebook_tqdm\n",
      "/root/anaconda3/envs/scgpt_new/lib/python3.10/site-packages/torch_npu/dynamo/__init__.py:18: UserWarning: Register eager implementation for the 'npu' backend of dynamo, as torch_npu was not compiled with torchair.\n",
      "  warnings.warn(\n",
      "/root/anaconda3/envs/scgpt_new/lib/python3.10/site-packages/torch_npu/contrib/transfer_to_npu.py:164: ImportWarning: \n",
      "    *************************************************************************************************************\n",
      "    The torch.Tensor.cuda and torch.nn.Module.cuda are replaced with torch.Tensor.npu and torch.nn.Module.npu now..\n",
      "    The torch.cuda.DoubleTensor is replaced with torch.npu.FloatTensor cause the double type is not supported now..\n",
      "    The backend in torch.distributed.init_process_group set to hccl now..\n",
      "    The torch.cuda.* and torch.cuda.amp.* are replaced with torch.npu.* and torch.npu.amp.* now..\n",
      "    The device parameters have been replaced with npu in the function below:\n",
      "    torch.logspace, torch.randint, torch.hann_window, torch.rand, torch.full_like, torch.ones_like, torch.rand_like, torch.randperm, torch.arange, torch.frombuffer, torch.normal, torch._empty_per_channel_affine_quantized, torch.empty_strided, torch.empty_like, torch.scalar_tensor, torch.tril_indices, torch.bartlett_window, torch.ones, torch.sparse_coo_tensor, torch.randn, torch.kaiser_window, torch.tensor, torch.triu_indices, torch.as_tensor, torch.zeros, torch.randint_like, torch.full, torch.eye, torch._sparse_csr_tensor_unsafe, torch.empty, torch._sparse_coo_tensor_unsafe, torch.blackman_window, torch.zeros_like, torch.range, torch.sparse_csr_tensor, torch.randn_like, torch.from_file, torch._cudnn_init_dropout_state, torch._empty_affine_quantized, torch.linspace, torch.hamming_window, torch.empty_quantized, torch._pin_memory, torch.Tensor.new_empty, torch.Tensor.new_empty_strided, torch.Tensor.new_full, torch.Tensor.new_ones, torch.Tensor.new_tensor, torch.Tensor.new_zeros, torch.Tensor.to, torch.nn.Module.to, torch.nn.Module.to_empty\n",
      "    *************************************************************************************************************\n",
      "    \n",
      "  warnings.warn(msg, ImportWarning)\n",
      "/root/riceFM/tutorials/../ricefm/model/model_main.py:30: UserWarning: flash_attn is not installed\n",
      "  warnings.warn(\"flash_attn is not installed\")\n",
      "/root/anaconda3/envs/scgpt_new/lib/python3.10/site-packages/scanpy/_settings.py:488: DeprecationWarning: `set_matplotlib_formats` is deprecated since IPython 7.23, directly use `matplotlib_inline.backend_inline.set_matplotlib_formats()`\n",
      "  IPython.display.set_matplotlib_formats(*ipython_format)\n"
     ]
    }
   ],
   "source": [
    "# %%\n",
    "import copy\n",
    "import gc\n",
    "import json\n",
    "import os\n",
    "from pathlib import Path\n",
    "import shutil\n",
    "import sys\n",
    "import time\n",
    "import traceback\n",
    "from typing import List, Tuple, Dict, Union, Optional\n",
    "import warnings\n",
    "import pandas as pd\n",
    "# from . import asyn\n",
    "import pickle\n",
    "import torch\n",
    "from anndata import AnnData\n",
    "import scanpy as sc\n",
    "# import scvi\n",
    "import seaborn as sns\n",
    "import numpy as np\n",
    "import wandb\n",
    "from scipy.sparse import issparse\n",
    "import matplotlib.pyplot as plt\n",
    "from torch import nn\n",
    "\n",
    "from torch_npu.contrib import transfer_to_npu\n",
    "import torch_npu\n",
    "\n",
    "from torch.nn import functional as F\n",
    "from torch.utils.data import Dataset, DataLoader\n",
    "from sklearn.model_selection import train_test_split\n",
    "from sklearn.metrics import adjusted_rand_score, normalized_mutual_info_score\n",
    "from torchtext.vocab import Vocab\n",
    "from torchtext._torchtext import (\n",
    "    Vocab as VocabPybind,\n",
    ")\n",
    "from sklearn.metrics import confusion_matrix\n",
    "\n",
    "sys.path.insert(0, \"../\")\n",
    "import ricefm as rfm\n",
    "from ricefm.model.model_main import TransformerModel, AdversarialDiscriminator\n",
    "from ricefm.tokenizer import tokenize_and_pad_batch, random_mask_value\n",
    "from ricefm.loss import (\n",
    "    masked_mse_loss,\n",
    "    masked_relative_error,\n",
    "    criterion_neg_log_bernoulli,\n",
    ")\n",
    "from ricefm.tokenizer.gene_tokenizer import GeneVocab\n",
    "from ricefm.preprocess import Preprocessor\n",
    "from ricefm import SubsetsBatchSampler\n",
    "from ricefm.utils import set_seed, category_str2int, eval_scib_metrics\n",
    "\n",
    "sc.set_figure_params(figsize=(6, 6))\n",
    "os.environ[\"KMP_WARNINGS\"] = \"off\"\n",
    "warnings.filterwarnings('ignore')"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "5f3b5d67",
   "metadata": {},
   "source": [
    "## Step1: Specify hyper-parameter setup for cell-type annotation task\n",
    "Listed below are some hyper-parameter recommendations for the cell-type task. Note that the CLS objective is on to facilitate cell-type classification."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "d07b5257",
   "metadata": {},
   "outputs": [],
   "source": [
    "hyperparameter_defaults = dict(\n",
    "    seed=0,\n",
    "    dataset_name=\"GSE232863\",\n",
    "    do_train=True,\n",
    "    load_model=\"/root/riceFM_save/eval-Nov05-18-46-2025\",\n",
    "    mask_ratio=0.0,\n",
    "    epochs=10,\n",
    "    n_bins=51,\n",
    "    MVC=False, # Masked value prediction for cell embedding\n",
    "    ecs_thres=0.0, # Elastic cell similarity objective, 0.0 to 1.0, 0.0 to disable\n",
    "    dab_weight=0.0,\n",
    "    lr=1e-4,\n",
    "    batch_size=32,\n",
    "    layer_size=256,\n",
    "    nlayers=6,  # number of nn.TransformerEncoderLayer in nn.TransformerEncoder\n",
    "    nhead=4,  # number of heads in nn.MultiheadAttention\n",
    "    dropout=0.2,  # dropout probability\n",
    "    schedule_ratio=0.9,  # ratio of epochs for learning rate schedule\n",
    "    save_eval_interval=5,\n",
    "    pre_norm=False,\n",
    "    amp=True,  # Automatic Mixed Precision\n",
    "    include_zero_gene = False,\n",
    "    freeze = False, #freeze\n",
    "    DSBN = False,  # Domain-spec batchnorm\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "94c08ee0",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "\u001b[34m\u001b[1mwandb\u001b[0m: \u001b[33mWARNING\u001b[0m `start_method` is deprecated and will be removed in a future version of wandb. This setting is currently non-functional and safely ignored.\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "{'seed': 0, 'dataset_name': 'GSE232863', 'do_train': True, 'load_model': '/root/riceFM_save/eval-Nov05-18-46-2025', 'mask_ratio': 0.0, 'epochs': 10, 'n_bins': 51, 'MVC': False, 'ecs_thres': 0.0, 'dab_weight': 0.0, 'lr': 0.0001, 'batch_size': 32, 'layer_size': 256, 'nlayers': 6, 'nhead': 4, 'dropout': 0.2, 'schedule_ratio': 0.9, 'save_eval_interval': 5, 'fast_transformer': True, 'pre_norm': False, 'amp': True, 'include_zero_gene': False, 'freeze': False, 'DSBN': False}\n"
     ]
    }
   ],
   "source": [
    "run = wandb.init(\n",
    "    config=hyperparameter_defaults,\n",
    "    project=\"ricefm\",\n",
    "    reinit=True,\n",
    "    settings=wandb.Settings(start_method=\"fork\"),\n",
    "    mode=\"disabled\"\n",
    ")\n",
    "config = wandb.config\n",
    "print(config)\n",
    "\n",
    "set_seed(config.seed)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "7d7890b7",
   "metadata": {},
   "outputs": [],
   "source": [
    "# settings for input and preprocessing\n",
    "pad_token = \"<pad>\"\n",
    "special_tokens = [pad_token, \"<cls>\", \"<eoc>\"]\n",
    "mask_ratio = config.mask_ratio\n",
    "mask_value = \"auto\"  # for masked values, now it should always be auto\n",
    "\n",
    "include_zero_gene = config.include_zero_gene  # if True, include zero genes among hvgs in the training\n",
    "max_seq_len = 3001\n",
    "n_bins = config.n_bins\n",
    "\n",
    "# input/output representation\n",
    "input_style = \"binned\"  # \"normed_raw\", \"log1p\", or \"binned\"\n",
    "output_style = \"binned\"  # \"normed_raw\", \"log1p\", or \"binned\"\n",
    "\n",
    "# settings for training\n",
    "MLM = False  # whether to use masked language modeling, currently it is always on.\n",
    "CLS = True  # celltype classification objective\n",
    "ADV = False  # Adversarial training for batch correction\n",
    "CCE = False  # Contrastive cell embedding objective\n",
    "MVC = config.MVC  # Masked value prediction for cell embedding\n",
    "ECS = config.ecs_thres > 0  # Elastic cell similarity objective\n",
    "DAB = False  # Domain adaptation by reverse backpropagation, set to 2 for separate optimizer\n",
    "INPUT_BATCH_LABELS = False  # TODO: have these help MLM and MVC, while not to classifier\n",
    "input_emb_style = \"continuous\"  # \"category\" or \"continuous\" or \"scaling\"\n",
    "cell_emb_style = \"cls\"  # \"avg-pool\" or \"w-pool\" or \"cls\"\n",
    "adv_E_delay_epochs = 0  # delay adversarial training on encoder for a few epochs\n",
    "adv_D_delay_epochs = 0\n",
    "mvc_decoder_style = \"inner product\"\n",
    "ecs_threshold = config.ecs_thres\n",
    "dab_weight = config.dab_weight\n",
    "\n",
    "explicit_zero_prob = MLM and include_zero_gene  # whether explicit bernoulli for zeros\n",
    "do_sample_in_train = False and explicit_zero_prob  # sample the bernoulli in training\n",
    "\n",
    "per_seq_batch_sample = False\n",
    "\n",
    "# settings for optimizer\n",
    "lr = config.lr  # TODO: test learning rate ratio between two tasks\n",
    "lr_ADV = 1e-3  # learning rate for discriminator, used when ADV is True\n",
    "batch_size = config.batch_size\n",
    "eval_batch_size = config.batch_size\n",
    "epochs = config.epochs\n",
    "schedule_interval = 1\n",
    "\n",
    "# settings for the model\n",
    "embsize = config.layer_size  # embedding dimension\n",
    "d_hid = config.layer_size  # dimension of the feedforward network in TransformerEncoder\n",
    "nlayers = config.nlayers  # number of TransformerEncoderLayer in TransformerEncoder\n",
    "nhead = config.nhead  # number of heads in nn.MultiheadAttention\n",
    "dropout = config.dropout  # dropout probability\n",
    "\n",
    "# logging\n",
    "log_interval = 100  # iterations\n",
    "save_eval_interval = config.save_eval_interval  # epochs\n",
    "do_eval_scib_metrics = True\n",
    "\n",
    "#sc--->0   st--->1\n",
    "mod_type = 0"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "17ff2309",
   "metadata": {},
   "outputs": [],
   "source": [
    "# %% validate settings\n",
    "assert input_style in [\"normed_raw\", \"log1p\", \"binned\"]\n",
    "assert output_style in [\"normed_raw\", \"log1p\", \"binned\"]\n",
    "assert input_emb_style in [\"category\", \"continuous\", \"scaling\"]\n",
    "if input_style == \"binned\":\n",
    "    if input_emb_style == \"scaling\":\n",
    "        raise ValueError(\"input_emb_style `scaling` is not supported for binned input.\")\n",
    "elif input_style == \"log1p\" or input_style == \"normed_raw\":\n",
    "    if input_emb_style == \"category\":\n",
    "        raise ValueError(\n",
    "            \"input_emb_style `category` is not supported for log1p or normed_raw input.\"\n",
    "        )\n",
    "\n",
    "if input_emb_style == \"category\":\n",
    "    mask_value = n_bins + 1\n",
    "    pad_value = n_bins  # for padding gene expr values\n",
    "    n_input_bins = n_bins + 2\n",
    "else:\n",
    "    mask_value = -1\n",
    "    pad_value = -2\n",
    "    n_input_bins = n_bins\n",
    "\n",
    "if ADV and DAB:\n",
    "    raise ValueError(\"ADV and DAB cannot be both True.\")\n",
    "DAB_separate_optim = True if DAB > 1 else False"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "cf7112d8",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "save to save/dev_GSE232863-Nov06-16-45\n"
     ]
    }
   ],
   "source": [
    "dataset_name = config.dataset_name\n",
    "save_dir = Path(f\"./save/dev_{dataset_name}-{time.strftime('%b%d-%H-%M')}/\")\n",
    "save_dir.mkdir(parents=True, exist_ok=True)\n",
    "print(f\"save to {save_dir}\")\n",
    "logger = rfm.logger\n",
    "rfm.utils.add_file_handler(logger, save_dir / \"run.log\")"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "37fc7002",
   "metadata": {},
   "source": [
    "## Step 2: Load and pre-process data\n",
    "We follow the standard scGPT data pre-processing pipelines for the cell-type annotation task. Note that since now we have two datasets at hand (i.e., reference and query data), the same pre-prpocessing steps need to be applied to both of them."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "95b50200",
   "metadata": {},
   "outputs": [],
   "source": [
    "adata = sc.read(\"/root/celltype_annotation/GSE232863-tissue_cluster_names_max3000/train_adata.h5ad\")\n",
    "adata_test = sc.read(\"/root/celltype_annotation/GSE232863-tissue_cluster_names_max3000/test_adata.h5ad\")\n",
    "adata.obs[\"celltype\"] = adata.obs[\"tissue_cluster_names\"].astype(\"category\")\n",
    "adata_test.obs[\"celltype\"] = adata_test.obs[\"tissue_cluster_names\"].astype(\"category\")\n",
    "adata.obs[\"batch_id\"]  = adata.obs[\"str_batch\"] = \"0\"\n",
    "adata_test.obs[\"batch_id\"]  = adata_test.obs[\"str_batch\"] = \"1\"   \n",
    "adata.obs['mod_type'] = mod_type\n",
    "adata_test.obs['mod_type'] = mod_type\n",
    "\n",
    "\n",
    "# adata.var.set_index(adata.var[\"gene_name\"], inplace=True)\n",
    "# adata_test.var.set_index(adata.var[\"gene_name\"], inplace=True)\n",
    "data_is_raw = True\n",
    "filter_gene_by_counts = False\n",
    "adata_test_raw = adata_test.copy()\n",
    "adata = adata.concatenate(adata_test, batch_key=\"str_batch\")\n",
    "                \n",
    "# make the batch category column\n",
    "batch_id_labels = adata.obs[\"str_batch\"].astype(\"category\").cat.codes.values\n",
    "adata.obs[\"batch_id\"] = batch_id_labels\n",
    "celltype_id_labels = adata.obs[\"celltype\"].astype(\"category\").cat.codes.values\n",
    "celltypes = adata.obs[\"celltype\"].unique()\n",
    "num_types = len(np.unique(celltype_id_labels))\n",
    "id2type = dict(enumerate(adata.obs[\"celltype\"].astype(\"category\").cat.categories))\n",
    "adata.obs[\"celltype_id\"] = celltype_id_labels\n",
    "adata.var[\"gene_name\"] = adata.var.index.tolist()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 8,
   "id": "0dc5a6ed",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "riceFM - INFO - match 25976/25976 genes in vocabulary of size 40158.\n",
      "riceFM - INFO - Resume model from /root/riceFM_save/eval-Nov05-18-46-2025/best_model.pt, the model args will override the config /root/riceFM_save/eval-Nov05-18-46-2025/args.json.\n"
     ]
    }
   ],
   "source": [
    "if config.load_model is not None:\n",
    "    model_dir = Path(config.load_model)\n",
    "    model_config_file = model_dir / \"args.json\"\n",
    "    model_file = model_dir / \"best_model.pt\"\n",
    "    vocab_file = model_dir / \"vocab.json\"\n",
    "\n",
    "    vocab = GeneVocab.from_file(vocab_file)\n",
    "    shutil.copy(vocab_file, save_dir / \"vocab.json\")\n",
    "    shutil.copy(model_config_file, save_dir / \"args.json\")\n",
    "    for s in special_tokens:\n",
    "        if s not in vocab:\n",
    "            vocab.append_token(s)\n",
    "\n",
    "    adata.var[\"id_in_vocab\"] = [\n",
    "        1 if gene in vocab else -1 for gene in adata.var[\"gene_name\"]\n",
    "    ]\n",
    "    gene_ids_in_vocab = np.array(adata.var[\"id_in_vocab\"])\n",
    "    logger.info(\n",
    "        f\"match {np.sum(gene_ids_in_vocab >= 0)}/{len(gene_ids_in_vocab)} genes \"\n",
    "        f\"in vocabulary of size {len(vocab)}.\"\n",
    "    )\n",
    "    adata = adata[:, adata.var[\"id_in_vocab\"] >= 0]\n",
    "\n",
    "    # model\n",
    "    with open(model_config_file, \"r\") as f:\n",
    "        model_configs = json.load(f)\n",
    "    logger.info(\n",
    "        f\"Resume model from {model_file}, the model args will override the \"\n",
    "        f\"config {model_config_file}.\"\n",
    "    )\n",
    "    embsize = model_configs[\"embsize\"]\n",
    "    nhead = model_configs[\"nheads\"]\n",
    "    d_hid = model_configs[\"d_hid\"]\n",
    "    nlayers = model_configs[\"nlayers\"]\n",
    "    n_layers_cls = model_configs[\"n_layers_cls\"]\n",
    "    "
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 9,
   "id": "d08757ed",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "riceFM - INFO - Filtering cells by counts ...\n",
      "riceFM - INFO - Normalizing total counts ...\n",
      "riceFM - INFO - Log1p transforming ...\n",
      "riceFM - INFO - Binning data ...\n",
      "riceFM - INFO - Filtering cells by counts ...\n",
      "riceFM - INFO - Normalizing total counts ...\n",
      "riceFM - INFO - Log1p transforming ...\n",
      "riceFM - INFO - Binning data ...\n"
     ]
    }
   ],
   "source": [
    "# set up the preprocessor, use the args to config the workflow\n",
    "preprocessor = Preprocessor(\n",
    "    use_key=\"X\",  # the key in adata.layers to use as raw data\n",
    "    filter_gene_by_counts=filter_gene_by_counts,  # step 1\n",
    "    filter_cell_by_counts=False,  # step 2\n",
    "    normalize_total=1e4,  # 3. whether to normalize the raw data and to what sum\n",
    "    result_normed_key=\"X_normed\",  # the key in adata.layers to store the normalized data\n",
    "    log1p=data_is_raw,  # 4. whether to log1p the normalized data\n",
    "    result_log1p_key=\"X_log1p\",\n",
    "    subset_hvg=False,  # 5. whether to subset the raw data to highly variable genes\n",
    "    hvg_flavor=\"seurat_v3\" if data_is_raw else \"cell_ranger\",\n",
    "    binning=n_bins,  # 6. whether to bin the raw data and to what number of bins\n",
    "    result_binned_key=\"X_binned\",  # the key in adata.layers to store the binned data\n",
    ")\n",
    "\n",
    "\n",
    "adata_test = adata[adata.obs[\"str_batch\"] == \"1\"]\n",
    "adata = adata[adata.obs[\"str_batch\"] == \"0\"]\n",
    "\n",
    "preprocessor(adata, batch_key=None)\n",
    "preprocessor(adata_test, batch_key=None)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 10,
   "id": "cbc1b20f",
   "metadata": {},
   "outputs": [],
   "source": [
    "input_layer_key = {  # the values of this map coorespond to the keys in preprocessing\n",
    "    \"normed_raw\": \"X_normed\",\n",
    "    \"log1p\": \"X_normed\",\n",
    "    \"binned\": \"X_binned\",\n",
    "}[input_style]\n",
    "all_counts = (\n",
    "    adata.layers[input_layer_key].A\n",
    "    if issparse(adata.layers[input_layer_key])\n",
    "    else adata.layers[input_layer_key]\n",
    ")\n",
    "genes = adata.var[\"gene_name\"].tolist()\n",
    "\n",
    "celltypes_labels = adata.obs[\"celltype_id\"].tolist()  # make sure count from 0\n",
    "celltypes_labels = np.array(celltypes_labels)\n",
    "\n",
    "batch_ids = adata.obs[\"batch_id\"].tolist()\n",
    "num_batch_types = len(set(batch_ids))\n",
    "batch_ids = np.array(batch_ids)\n",
    "\n",
    "mod_types = adata.obs[\"mod_type\"].tolist()\n",
    "mod_types = np.array(mod_types)\n",
    "\n",
    "(\n",
    "    train_data,\n",
    "    valid_data,\n",
    "    train_celltype_labels,\n",
    "    valid_celltype_labels,\n",
    "    train_batch_labels,\n",
    "    valid_batch_labels,\n",
    "    train_mod_labels,\n",
    "    valid_mod_labels,\n",
    ") = train_test_split(\n",
    "    all_counts, celltypes_labels, batch_ids, mod_types, test_size=0.1, shuffle=True\n",
    ")\n",
    "\n"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 11,
   "id": "4cd701b1",
   "metadata": {},
   "outputs": [],
   "source": [
    "if config.load_model is None:\n",
    "    vocab = Vocab(\n",
    "        VocabPybind(genes + special_tokens, None)\n",
    "    )  # bidirectional lookup [gene <-> int]\n",
    "vocab.set_default_index(vocab[\"<pad>\"])\n",
    "gene_ids = np.array(vocab(genes), dtype=int)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 12,
   "id": "818bfcc0",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "riceFM - INFO - train set number of samples: 31177, \n",
      "\t feature length: 3001\n",
      "riceFM - INFO - valid set number of samples: 3465, \n",
      "\t feature length: 3001\n"
     ]
    }
   ],
   "source": [
    "tokenized_train = tokenize_and_pad_batch(\n",
    "    train_data,\n",
    "    gene_ids,\n",
    "    max_len=max_seq_len,\n",
    "    vocab=vocab,\n",
    "    pad_token=pad_token,\n",
    "    pad_value=pad_value,\n",
    "    append_cls=True,  # append <cls> token at the beginning\n",
    "    include_zero_gene=include_zero_gene,\n",
    ")\n",
    "tokenized_valid = tokenize_and_pad_batch(\n",
    "    valid_data,\n",
    "    gene_ids,\n",
    "    max_len=max_seq_len,\n",
    "    vocab=vocab,\n",
    "    pad_token=pad_token,\n",
    "    pad_value=pad_value,\n",
    "    append_cls=True,\n",
    "    include_zero_gene=include_zero_gene,\n",
    ")\n",
    "logger.info(\n",
    "    f\"train set number of samples: {tokenized_train['genes'].shape[0]}, \"\n",
    "    f\"\\n\\t feature length: {tokenized_train['genes'].shape[1]}\"\n",
    ")\n",
    "logger.info(\n",
    "    f\"valid set number of samples: {tokenized_valid['genes'].shape[0]}, \"\n",
    "    f\"\\n\\t feature length: {tokenized_valid['genes'].shape[1]}\"\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 13,
   "id": "37a80818",
   "metadata": {},
   "outputs": [],
   "source": [
    "def prepare_data(sort_seq_batch=False) -> Tuple[Dict[str, torch.Tensor]]:\n",
    "    masked_values_train = random_mask_value(\n",
    "        tokenized_train[\"values\"],\n",
    "        mask_ratio=mask_ratio,\n",
    "        mask_value=mask_value,\n",
    "        pad_value=pad_value,\n",
    "    )\n",
    "    masked_values_valid = random_mask_value(\n",
    "        tokenized_valid[\"values\"],\n",
    "        mask_ratio=mask_ratio,\n",
    "        mask_value=mask_value,\n",
    "        pad_value=pad_value,\n",
    "    )\n",
    "    print(\n",
    "        f\"random masking at epoch {epoch:3d}, ratio of masked values in train: \",\n",
    "        f\"{(masked_values_train == mask_value).sum() / (masked_values_train - pad_value).count_nonzero():.4f}\",\n",
    "    )\n",
    "\n",
    "    input_gene_ids_train, input_gene_ids_valid = (\n",
    "        tokenized_train[\"genes\"],\n",
    "        tokenized_valid[\"genes\"],\n",
    "    )\n",
    "    input_values_train, input_values_valid = masked_values_train, masked_values_valid\n",
    "    target_values_train, target_values_valid = (\n",
    "        tokenized_train[\"values\"],\n",
    "        tokenized_valid[\"values\"],\n",
    "    )\n",
    "\n",
    "    tensor_batch_labels_train = torch.from_numpy(train_batch_labels).long()\n",
    "    tensor_batch_labels_valid = torch.from_numpy(valid_batch_labels).long()\n",
    "\n",
    "    tensor_mod_labels_train = torch.from_numpy(train_mod_labels).long()\n",
    "    tensor_mod_labels_valid = torch.from_numpy(valid_mod_labels).long()\n",
    "\n",
    "    tensor_celltype_labels_train = torch.from_numpy(train_celltype_labels).long()\n",
    "    tensor_celltype_labels_valid = torch.from_numpy(valid_celltype_labels).long()\n",
    "\n",
    "    if sort_seq_batch:  # TODO: update to random pick seq source in each traning batch\n",
    "        train_sort_ids = np.argsort(train_batch_labels)\n",
    "        input_gene_ids_train = input_gene_ids_train[train_sort_ids]\n",
    "        input_values_train = input_values_train[train_sort_ids]\n",
    "        target_values_train = target_values_train[train_sort_ids]\n",
    "        tensor_batch_labels_train = tensor_batch_labels_train[train_sort_ids]\n",
    "        tensor_mod_labels_train = tensor_mod_labels_train[train_sort_ids]\n",
    "        tensor_celltype_labels_train = tensor_celltype_labels_train[train_sort_ids]\n",
    "\n",
    "        valid_sort_ids = np.argsort(valid_batch_labels)\n",
    "        input_gene_ids_valid = input_gene_ids_valid[valid_sort_ids]\n",
    "        input_values_valid = input_values_valid[valid_sort_ids]\n",
    "        target_values_valid = target_values_valid[valid_sort_ids]\n",
    "        tensor_batch_labels_valid = tensor_batch_labels_valid[valid_sort_ids]\n",
    "        tensor_mod_labels_valid = tensor_mod_labels_valid[valid_sort_ids]\n",
    "        tensor_celltype_labels_valid = tensor_celltype_labels_valid[valid_sort_ids]\n",
    "\n",
    "    train_data_pt = {\n",
    "        \"gene_ids\": input_gene_ids_train,\n",
    "        \"values\": input_values_train,\n",
    "        \"target_values\": target_values_train,\n",
    "        \"batch_labels\": tensor_batch_labels_train,\n",
    "        \"mod_labels\": tensor_mod_labels_train,\n",
    "        \"celltype_labels\": tensor_celltype_labels_train,\n",
    "    }\n",
    "    valid_data_pt = {\n",
    "        \"gene_ids\": input_gene_ids_valid,\n",
    "        \"values\": input_values_valid,\n",
    "        \"target_values\": target_values_valid,\n",
    "        \"batch_labels\": tensor_batch_labels_valid,\n",
    "        \"mod_labels\": tensor_mod_labels_valid,\n",
    "        \"celltype_labels\": tensor_celltype_labels_valid,\n",
    "    }\n",
    "\n",
    "    return train_data_pt, valid_data_pt\n",
    "\n",
    "\n",
    "# dataset\n",
    "class SeqDataset(Dataset):\n",
    "    def __init__(self, data: Dict[str, torch.Tensor]):\n",
    "        self.data = data\n",
    "\n",
    "    def __len__(self):\n",
    "        return self.data[\"gene_ids\"].shape[0]\n",
    "\n",
    "    def __getitem__(self, idx):\n",
    "        return {k: v[idx] for k, v in self.data.items()}\n",
    "\n",
    "\n",
    "# data_loader\n",
    "def prepare_dataloader(\n",
    "    data_pt: Dict[str, torch.Tensor],\n",
    "    batch_size: int,\n",
    "    shuffle: bool = False,\n",
    "    intra_domain_shuffle: bool = False,\n",
    "    drop_last: bool = False,\n",
    "    num_workers: int = 0,\n",
    ") -> DataLoader:\n",
    "    if num_workers == 0:\n",
    "        num_workers = min(len(os.sched_getaffinity(0)), batch_size // 2)\n",
    "\n",
    "    dataset = SeqDataset(data_pt)\n",
    "\n",
    "    if per_seq_batch_sample:\n",
    "        # find the indices of samples in each seq batch\n",
    "        subsets = []\n",
    "        batch_labels_array = data_pt[\"batch_labels\"].numpy()\n",
    "        for batch_label in np.unique(batch_labels_array):\n",
    "            batch_indices = np.where(batch_labels_array == batch_label)[0].tolist()\n",
    "            subsets.append(batch_indices)\n",
    "        data_loader = DataLoader(\n",
    "            dataset=dataset,\n",
    "            batch_sampler=SubsetsBatchSampler(\n",
    "                subsets,\n",
    "                batch_size,\n",
    "                intra_subset_shuffle=intra_domain_shuffle,\n",
    "                inter_subset_shuffle=shuffle,\n",
    "                drop_last=drop_last,\n",
    "            ),\n",
    "            num_workers=num_workers,\n",
    "            pin_memory=True,\n",
    "        )\n",
    "        return data_loader\n",
    "\n",
    "    data_loader = DataLoader(\n",
    "        dataset=dataset,\n",
    "        batch_size=batch_size,\n",
    "        shuffle=shuffle,\n",
    "        drop_last=drop_last,\n",
    "        num_workers=num_workers,\n",
    "        pin_memory=True,\n",
    "    )\n",
    "    return data_loader\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "77105fda",
   "metadata": {},
   "source": [
    "## Step 3: Load the pre-trained scGPT model"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "219bb9db",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "riceFM - INFO - Loading params encoder.embedding.weight with shape torch.Size([40158, 256])\n",
      "riceFM - INFO - Loading params encoder.enc_norm.weight with shape torch.Size([256])\n",
      "riceFM - INFO - Loading params encoder.enc_norm.bias with shape torch.Size([256])\n",
      "riceFM - INFO - Loading params value_encoder.linear1.weight with shape torch.Size([256, 1])\n",
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      "--------------------\n",
      "name: encoder.embedding.weight\n",
      "--------------------\n",
      "name: encoder.enc_norm.weight\n",
      "--------------------\n",
      "name: encoder.enc_norm.bias\n",
      "--------------------\n",
      "name: value_encoder.linear1.weight\n",
      "--------------------\n",
      "name: value_encoder.linear1.bias\n",
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      "name: value_encoder.linear2.weight\n",
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      "name: value_encoder.linear2.bias\n",
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      "name: value_encoder.norm.weight\n",
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      "name: value_encoder.norm.bias\n",
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      "name: mod_encoder.embedding.weight\n",
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      "name: mod_encoder.enc_norm.weight\n",
      "--------------------\n",
      "name: mod_encoder.enc_norm.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.0.self_attn.in_proj_weight\n",
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      "name: transformer_encoder.layers.0.self_attn.in_proj_bias\n",
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      "--------------------\n",
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      "name: transformer_encoder.layers.0.linear1.weight\n",
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      "--------------------\n",
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      "name: transformer_encoder.layers.1.linear1.bias\n",
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      "name: transformer_encoder.layers.2.self_attn.in_proj_bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.2.self_attn.out_proj.weight\n",
      "--------------------\n",
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      "--------------------\n",
      "name: transformer_encoder.layers.2.linear1.weight\n",
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      "name: transformer_encoder.layers.2.linear1.bias\n",
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      "name: transformer_encoder.layers.2.linear2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.2.linear2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.2.norm1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.2.norm1.bias\n",
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      "name: transformer_encoder.layers.2.norm2.weight\n",
      "--------------------\n",
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      "--------------------\n",
      "name: transformer_encoder.layers.3.self_attn.in_proj_weight\n",
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      "name: transformer_encoder.layers.3.self_attn.in_proj_bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.self_attn.out_proj.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.self_attn.out_proj.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.linear1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.linear1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.linear2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.linear2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.norm1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.norm1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.norm2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.3.norm2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.self_attn.in_proj_weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.self_attn.in_proj_bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.self_attn.out_proj.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.self_attn.out_proj.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.linear1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.linear1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.linear2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.linear2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.norm1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.norm1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.norm2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.4.norm2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.self_attn.in_proj_weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.self_attn.in_proj_bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.self_attn.out_proj.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.self_attn.out_proj.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.linear1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.linear1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.linear2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.linear2.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.norm1.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.norm1.bias\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.norm2.weight\n",
      "--------------------\n",
      "name: transformer_encoder.layers.5.norm2.bias\n",
      "--------------------\n",
      "name: decoder.fc.0.weight\n",
      "--------------------\n",
      "name: decoder.fc.0.bias\n",
      "--------------------\n",
      "name: decoder.fc.2.weight\n",
      "--------------------\n",
      "name: decoder.fc.2.bias\n",
      "--------------------\n",
      "name: decoder.fc.4.weight\n",
      "--------------------\n",
      "name: decoder.fc.4.bias\n",
      "--------------------\n",
      "name: cls_decoder._decoder.0.weight\n",
      "--------------------\n",
      "name: cls_decoder._decoder.0.bias\n",
      "--------------------\n",
      "name: cls_decoder._decoder.2.weight\n",
      "--------------------\n",
      "name: cls_decoder._decoder.2.bias\n",
      "--------------------\n",
      "name: cls_decoder._decoder.3.weight\n",
      "--------------------\n",
      "name: cls_decoder._decoder.3.bias\n",
      "--------------------\n",
      "name: cls_decoder._decoder.5.weight\n",
      "--------------------\n",
      "name: cls_decoder._decoder.5.bias\n",
      "--------------------\n",
      "name: cls_decoder.out_layer.weight\n",
      "--------------------\n",
      "name: cls_decoder.out_layer.bias\n",
      "riceFM - INFO - Total Pre freeze Params 13002297\n",
      "riceFM - INFO - Total Post freeze Params 13002297\n"
     ]
    }
   ],
   "source": [
    "# device = torch.device(\"cuda\" if torch.cuda.is_available() else \"cpu\")\n",
    "device = torch.device(\"npu:0\" if torch.npu.is_available() else \"cpu\")\n",
    "torch.npu.set_device(device)\n",
    "\n",
    "ntokens = len(vocab)  # size of vocabulary\n",
    "model = TransformerModel(\n",
    "    ntokens,\n",
    "    embsize,\n",
    "    nhead,\n",
    "    d_hid,\n",
    "    nlayers,\n",
    "    nlayers_cls=3,\n",
    "    n_cls=num_types if CLS else 1,\n",
    "    vocab=vocab,\n",
    "    dropout=dropout,\n",
    "    pad_token=pad_token,\n",
    "    pad_value=pad_value,\n",
    "    do_mvc=MVC,\n",
    "    do_dab=DAB,\n",
    "    use_batch_labels=INPUT_BATCH_LABELS,\n",
    "    num_batch_labels=num_batch_types,\n",
    "    domain_spec_batchnorm=config.DSBN,\n",
    "    input_emb_style=input_emb_style,\n",
    "    n_input_bins=n_input_bins,\n",
    "    cell_emb_style=cell_emb_style,\n",
    "    mvc_decoder_style=mvc_decoder_style,\n",
    "    ecs_threshold=ecs_threshold,\n",
    "    explicit_zero_prob=explicit_zero_prob,\n",
    "    pre_norm=config.pre_norm,\n",
    ")\n",
    "if config.load_model is not None:\n",
    "    try:\n",
    "        model.load_state_dict(torch.load(model_file))\n",
    "        logger.info(f\"Loading all model params from {model_file}\")\n",
    "    except:\n",
    "        # only load params that are in the model and match the size\n",
    "        model_dict = model.state_dict()\n",
    "        pretrained_dict = torch.load(model_file)\n",
    "        pretrained_dict = {\n",
    "            k: v\n",
    "            for k, v in pretrained_dict.items()\n",
    "            if k in model_dict and v.shape == model_dict[k].shape\n",
    "        }\n",
    "        for k, v in pretrained_dict.items():\n",
    "            logger.info(f\"Loading params {k} with shape {v.shape}\")\n",
    "        model_dict.update(pretrained_dict)\n",
    "        model.load_state_dict(model_dict)\n",
    "\n",
    "pre_freeze_param_count = sum(dict((p.data_ptr(), p.numel()) for p in model.parameters() if p.requires_grad).values())\n",
    "\n",
    "# Freeze all pre-decoder weights\n",
    "for name, para in model.named_parameters():\n",
    "    print(\"-\"*20)\n",
    "    print(f\"name: {name}\")\n",
    "    if config.freeze and \"encoder\" in name and \"transformer_encoder\" not in name:\n",
    "    # if config.freeze and \"encoder\" in name:\n",
    "        print(f\"freezing weights for: {name}\")\n",
    "        para.requires_grad = False\n",
    "\n",
    "post_freeze_param_count = sum(dict((p.data_ptr(), p.numel()) for p in model.parameters() if p.requires_grad).values())\n",
    "\n",
    "logger.info(f\"Total Pre freeze Params {(pre_freeze_param_count )}\")\n",
    "logger.info(f\"Total Post freeze Params {(post_freeze_param_count )}\")\n",
    "wandb.log(\n",
    "        {\n",
    "            \"info/pre_freeze_param_count\": pre_freeze_param_count,\n",
    "            \"info/post_freeze_param_count\": post_freeze_param_count,\n",
    "        },\n",
    ")\n",
    "\n",
    "model.to(device)\n",
    "wandb.watch(model)\n",
    "\n",
    "if ADV:\n",
    "    discriminator = AdversarialDiscriminator(\n",
    "        d_model=embsize,\n",
    "        n_cls=num_batch_types,\n",
    "    ).to(device)\n"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 15,
   "id": "1e4ea79e",
   "metadata": {},
   "outputs": [],
   "source": [
    "criterion = masked_mse_loss\n",
    "criterion_cls = nn.CrossEntropyLoss()\n",
    "criterion_dab = nn.CrossEntropyLoss()\n",
    "optimizer = torch.optim.Adam(\n",
    "    model.parameters(), lr=lr, eps=1e-4 if config.amp else 1e-8\n",
    ")\n",
    "scheduler = torch.optim.lr_scheduler.StepLR(\n",
    "    optimizer, schedule_interval, gamma=config.schedule_ratio\n",
    ")\n",
    "if DAB_separate_optim:\n",
    "    optimizer_dab = torch.optim.Adam(model.parameters(), lr=lr)\n",
    "    scheduler_dab = torch.optim.lr_scheduler.StepLR(\n",
    "        optimizer_dab, schedule_interval, gamma=config.schedule_ratio\n",
    "    )\n",
    "if ADV:\n",
    "    criterion_adv = nn.CrossEntropyLoss()  # consider using label smoothing\n",
    "    optimizer_E = torch.optim.Adam(model.parameters(), lr=lr_ADV)\n",
    "    scheduler_E = torch.optim.lr_scheduler.StepLR(\n",
    "        optimizer_E, schedule_interval, gamma=config.schedule_ratio\n",
    "    )\n",
    "    optimizer_D = torch.optim.Adam(discriminator.parameters(), lr=lr_ADV)\n",
    "    scheduler_D = torch.optim.lr_scheduler.StepLR(\n",
    "        optimizer_D, schedule_interval, gamma=config.schedule_ratio\n",
    "    )\n",
    "\n",
    "scaler = torch.cuda.amp.GradScaler(enabled=config.amp)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 19,
   "id": "b734269a",
   "metadata": {},
   "outputs": [],
   "source": [
    "def train(model: nn.Module, loader: DataLoader) -> None:\n",
    "    \"\"\"\n",
    "    Train the model for one epoch.\n",
    "    \"\"\"\n",
    "    model.train()\n",
    "    (\n",
    "        total_loss,\n",
    "        total_mse,\n",
    "        total_cls,\n",
    "        total_cce,\n",
    "        total_mvc,\n",
    "        total_ecs,\n",
    "        total_dab,\n",
    "        total_adv_E,\n",
    "        total_adv_D,\n",
    "        total_zero_log_prob,\n",
    "        total_mvc_zero_log_prob,\n",
    "    ) = (0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0)\n",
    "    total_error = 0.0\n",
    "    start_time = time.time()\n",
    "\n",
    "    num_batches = len(loader)\n",
    "    for batch, batch_data in enumerate(loader):\n",
    "        input_gene_ids = batch_data[\"gene_ids\"].to(device)\n",
    "        input_values = batch_data[\"values\"].to(device)\n",
    "        target_values = batch_data[\"target_values\"].to(device)\n",
    "        batch_labels = batch_data[\"batch_labels\"].to(device)\n",
    "        mod_labels = batch_data[\"mod_labels\"].to(device)\n",
    "        celltype_labels = batch_data[\"celltype_labels\"].to(device)\n",
    "\n",
    "        # batch_labels=batch_labels if INPUT_BATCH_LABELS or config.DSBN else None\n",
    "        # print(batch_labels)  #\"None\"\n",
    "        # print(config.DSBN)   #False\n",
    "\n",
    "        src_key_padding_mask = input_gene_ids.eq(vocab[pad_token])\n",
    "        with torch.cuda.amp.autocast(enabled=config.amp):\n",
    "            output_dict = model(\n",
    "                input_gene_ids,\n",
    "                input_values,\n",
    "                src_key_padding_mask=src_key_padding_mask,\n",
    "                mod_types=mod_labels,\n",
    "                batch_labels=batch_labels if INPUT_BATCH_LABELS or config.DSBN else None,\n",
    "                CLS=CLS,\n",
    "                CCE=CCE,\n",
    "                MVC=MVC,\n",
    "                ECS=ECS,\n",
    "                do_sample=do_sample_in_train,\n",
    "                #generative_training=False\n",
    "            )\n",
    "\n",
    "            masked_positions = input_values.eq(mask_value)  # the postions to predict\n",
    "            loss = 0.0\n",
    "            metrics_to_log = {}\n",
    "            if MLM:\n",
    "                loss_mse = criterion(\n",
    "                    output_dict[\"mlm_output\"], target_values, masked_positions\n",
    "                )\n",
    "                loss = loss + loss_mse\n",
    "                metrics_to_log = {\"train/mse\": loss_mse.item()}\n",
    "            if explicit_zero_prob:\n",
    "                loss_zero_log_prob = criterion_neg_log_bernoulli(\n",
    "                    output_dict[\"mlm_zero_probs\"], target_values, masked_positions\n",
    "                )\n",
    "                loss = loss + loss_zero_log_prob\n",
    "                metrics_to_log.update({\"train/nzlp\": loss_zero_log_prob.item()})\n",
    "            if CLS:\n",
    "                loss_cls = criterion_cls(output_dict[\"cls_output\"], celltype_labels)\n",
    "                loss = loss + loss_cls\n",
    "                metrics_to_log.update({\"train/cls\": loss_cls.item()})\n",
    "\n",
    "                error_rate = 1 - (\n",
    "                    (output_dict[\"cls_output\"].argmax(1) == celltype_labels)\n",
    "                    .sum()\n",
    "                    .item()\n",
    "                ) / celltype_labels.size(0)\n",
    "            if CCE:\n",
    "                loss_cce = 10 * output_dict[\"loss_cce\"]\n",
    "                loss = loss + loss_cce\n",
    "                metrics_to_log.update({\"train/cce\": loss_cce.item()})\n",
    "            if MVC:\n",
    "                loss_mvc = criterion(\n",
    "                    output_dict[\"mvc_output\"], target_values, masked_positions\n",
    "                )\n",
    "                loss = loss + loss_mvc\n",
    "                metrics_to_log.update({\"train/mvc\": loss_mvc.item()})\n",
    "            if MVC and explicit_zero_prob:\n",
    "                loss_mvc_zero_log_prob = criterion_neg_log_bernoulli(\n",
    "                    output_dict[\"mvc_zero_probs\"], target_values, masked_positions\n",
    "                )\n",
    "                loss = loss + loss_mvc_zero_log_prob\n",
    "                metrics_to_log.update({\"train/mvc_nzlp\": loss_mvc_zero_log_prob.item()})\n",
    "            if ECS:\n",
    "                loss_ecs = 10 * output_dict[\"loss_ecs\"]\n",
    "                loss = loss + loss_ecs\n",
    "                metrics_to_log.update({\"train/ecs\": loss_ecs.item()})\n",
    "            if DAB:\n",
    "                # try weighting and separate optimizer\n",
    "                loss_dab = criterion_dab(output_dict[\"dab_output\"], batch_labels)\n",
    "                loss = loss + dab_weight * loss_dab\n",
    "                metrics_to_log.update({\"train/dab\": loss_dab.item()})\n",
    "\n",
    "        model.zero_grad()\n",
    "        scaler.scale(loss).backward()\n",
    "        scaler.unscale_(optimizer)\n",
    "        with warnings.catch_warnings(record=True) as w:\n",
    "            warnings.filterwarnings(\"always\")\n",
    "            torch.nn.utils.clip_grad_norm_(\n",
    "                model.parameters(),\n",
    "                1.0,\n",
    "                error_if_nonfinite=False if scaler.is_enabled() else True,\n",
    "            )\n",
    "            if len(w) > 0:\n",
    "                logger.warning(\n",
    "                    f\"Found infinite gradient. This may be caused by the gradient \"\n",
    "                    f\"scaler. The current scale is {scaler.get_scale()}. This warning \"\n",
    "                    \"can be ignored if no longer occurs after autoscaling of the scaler.\"\n",
    "                )\n",
    "        scaler.step(optimizer)\n",
    "        scaler.update()\n",
    "\n",
    "        if ADV:\n",
    "            # rerun the model for adversarial training\n",
    "            output_dict = model(\n",
    "                input_gene_ids,\n",
    "                input_values,\n",
    "                src_key_padding_mask=src_key_padding_mask,\n",
    "                batch_labels=batch_labels if INPUT_BATCH_LABELS or config.DSBN else None,\n",
    "                CLS=CLS,\n",
    "                CCE=CCE,\n",
    "                MVC=MVC,\n",
    "                ECS=ECS,\n",
    "                do_sample=do_sample_in_train,\n",
    "                #generative_training=False\n",
    "            )\n",
    "\n",
    "            # TRAINING DISCRIMINATOR\n",
    "            loss_adv_D = criterion_adv(\n",
    "                discriminator(output_dict[\"cell_emb\"].detach()), batch_labels\n",
    "            )\n",
    "            if epoch > adv_D_delay_epochs:\n",
    "                discriminator.zero_grad()\n",
    "                loss_adv_D.backward()\n",
    "                optimizer_D.step()\n",
    "\n",
    "            # TRAINING ENCODER\n",
    "            loss_adv_E = -criterion_adv(\n",
    "                discriminator(output_dict[\"cell_emb\"]), batch_labels\n",
    "            )\n",
    "            # NOTE: the loss is negative here because we want to maximize\n",
    "            # the cross_entropy_loss, in other words, disguise against the discriminator\n",
    "            if epoch > adv_E_delay_epochs:\n",
    "                model.zero_grad()\n",
    "                discriminator.zero_grad()\n",
    "                loss_adv_E.backward()\n",
    "                optimizer_E.step()\n",
    "\n",
    "        wandb.log(metrics_to_log)\n",
    "\n",
    "        total_loss += loss.item()\n",
    "        total_mse += loss_mse.item() if MLM else 0.0\n",
    "        total_cls += loss_cls.item() if CLS else 0.0\n",
    "        total_cce += loss_cce.item() if CCE else 0.0\n",
    "        total_mvc += loss_mvc.item() if MVC else 0.0\n",
    "        total_ecs += loss_ecs.item() if ECS else 0.0\n",
    "        total_dab += loss_dab.item() if DAB else 0.0\n",
    "        total_adv_E += loss_adv_E.item() if ADV else 0.0\n",
    "        total_adv_D += loss_adv_D.item() if ADV else 0.0\n",
    "        total_zero_log_prob += loss_zero_log_prob.item() if explicit_zero_prob else 0.0\n",
    "        total_mvc_zero_log_prob += (\n",
    "            loss_mvc_zero_log_prob.item() if MVC and explicit_zero_prob else 0.0\n",
    "        )\n",
    "        total_error += error_rate\n",
    "        if batch % log_interval == 0 and batch > 0:\n",
    "            lr = scheduler.get_last_lr()[0]\n",
    "            ms_per_batch = (time.time() - start_time) * 1000 / log_interval\n",
    "            cur_loss = total_loss / log_interval\n",
    "            cur_mse = total_mse / log_interval\n",
    "            cur_cls = total_cls / log_interval if CLS else 0.0\n",
    "            cur_cce = total_cce / log_interval if CCE else 0.0\n",
    "            cur_mvc = total_mvc / log_interval if MVC else 0.0\n",
    "            cur_ecs = total_ecs / log_interval if ECS else 0.0\n",
    "            cur_dab = total_dab / log_interval if DAB else 0.0\n",
    "            cur_adv_E = total_adv_E / log_interval if ADV else 0.0\n",
    "            cur_adv_D = total_adv_D / log_interval if ADV else 0.0\n",
    "            cur_zero_log_prob = (\n",
    "                total_zero_log_prob / log_interval if explicit_zero_prob else 0.0\n",
    "            )\n",
    "            cur_mvc_zero_log_prob = (\n",
    "                total_mvc_zero_log_prob / log_interval\n",
    "                if MVC and explicit_zero_prob\n",
    "                else 0.0\n",
    "            )\n",
    "            cur_error = total_error / log_interval\n",
    "            # ppl = math.exp(cur_loss)\n",
    "            logger.info(\n",
    "                f\"| epoch {epoch:3d} | {batch:3d}/{num_batches:3d} batches | \"\n",
    "                f\"lr {lr:05.5f} | ms/batch {ms_per_batch:5.2f} | \"\n",
    "                f\"loss {cur_loss:5.2f} | \"\n",
    "                + (f\"mse {cur_mse:5.2f} | mre {cur_error:5.2f} |\" if MLM else \"\")\n",
    "                + (f\"cls {cur_cls:5.2f} | \" if CLS else \"\")\n",
    "                + (f\"err {cur_error:5.2f} | \" if CLS else \"\")\n",
    "                + (f\"cce {cur_cce:5.2f} |\" if CCE else \"\")\n",
    "                + (f\"mvc {cur_mvc:5.2f} |\" if MVC else \"\")\n",
    "                + (f\"ecs {cur_ecs:5.2f} |\" if ECS else \"\")\n",
    "                + (f\"dab {cur_dab:5.2f} |\" if DAB else \"\")\n",
    "                + (f\"adv_E {cur_adv_E:5.2f} |\" if ADV else \"\")\n",
    "                + (f\"adv_D {cur_adv_D:5.2f} |\" if ADV else \"\")\n",
    "                + (f\"nzlp {cur_zero_log_prob:5.2f} |\" if explicit_zero_prob else \"\")\n",
    "                + (\n",
    "                    f\"mvc_nzlp {cur_mvc_zero_log_prob:5.2f} |\"\n",
    "                    if MVC and explicit_zero_prob\n",
    "                    else \"\"\n",
    "                )\n",
    "            )\n",
    "            total_loss = 0\n",
    "            total_mse = 0\n",
    "            total_cls = 0\n",
    "            total_cce = 0\n",
    "            total_mvc = 0\n",
    "            total_ecs = 0\n",
    "            total_dab = 0\n",
    "            total_adv_E = 0\n",
    "            total_adv_D = 0\n",
    "            total_zero_log_prob = 0\n",
    "            total_mvc_zero_log_prob = 0\n",
    "            total_error = 0\n",
    "            start_time = time.time()\n",
    "\n",
    "\n",
    "def define_wandb_metrcis():\n",
    "    wandb.define_metric(\"valid/mse\", summary=\"min\", step_metric=\"epoch\")\n",
    "    wandb.define_metric(\"valid/mre\", summary=\"min\", step_metric=\"epoch\")\n",
    "    wandb.define_metric(\"valid/dab\", summary=\"min\", step_metric=\"epoch\")\n",
    "    wandb.define_metric(\"valid/sum_mse_dab\", summary=\"min\", step_metric=\"epoch\")\n",
    "    wandb.define_metric(\"test/avg_bio\", summary=\"max\")\n",
    "\n",
    "\n",
    "def evaluate(model: nn.Module, loader: DataLoader, return_raw: bool = False) -> float:\n",
    "    \"\"\"\n",
    "    Evaluate the model on the evaluation data.\n",
    "    \"\"\"\n",
    "    model.eval()\n",
    "    total_loss = 0.0\n",
    "    total_error = 0.0\n",
    "    total_dab = 0.0\n",
    "    total_num = 0\n",
    "    predictions = []\n",
    "    # with torch.no_grad():\n",
    "    for batch_data in loader:\n",
    "        input_gene_ids = batch_data[\"gene_ids\"].to(device)\n",
    "        input_values = batch_data[\"values\"].to(device)\n",
    "        target_values = batch_data[\"target_values\"].to(device)\n",
    "        batch_labels = batch_data[\"batch_labels\"].to(device)\n",
    "        mod_labels = batch_data[\"mod_labels\"].to(device)\n",
    "        celltype_labels = batch_data[\"celltype_labels\"].to(device)\n",
    "\n",
    "        src_key_padding_mask = input_gene_ids.eq(vocab[pad_token])\n",
    "        with torch.cuda.amp.autocast(enabled=config.amp):\n",
    "            output_dict = model(\n",
    "                input_gene_ids,\n",
    "                input_values,\n",
    "                src_key_padding_mask=src_key_padding_mask,\n",
    "                mod_types=mod_labels,\n",
    "                batch_labels=batch_labels if INPUT_BATCH_LABELS or config.DSBN else None,\n",
    "                CLS=CLS,  # evaluation does not need CLS or CCE\n",
    "                CCE=False,\n",
    "                MVC=False,\n",
    "                ECS=False,\n",
    "                do_sample=do_sample_in_train,\n",
    "                #generative_training = False,\n",
    "            )\n",
    "            output_values = output_dict[\"cls_output\"]\n",
    "            loss = criterion_cls(output_values, celltype_labels)\n",
    "\n",
    "            if DAB:\n",
    "                loss_dab = criterion_dab(output_dict[\"dab_output\"], batch_labels)\n",
    "\n",
    "        total_loss += loss.item() * len(input_gene_ids)\n",
    "        accuracy = (output_values.argmax(1) == celltype_labels).sum().item()\n",
    "        total_error += (1 - accuracy / len(input_gene_ids)) * len(input_gene_ids)\n",
    "        total_dab += loss_dab.item() * len(input_gene_ids) if DAB else 0.0\n",
    "        total_num += len(input_gene_ids)\n",
    "        preds = output_values.argmax(1).cpu().numpy()\n",
    "        predictions.append(preds)\n",
    "\n",
    "    # wandb.log(\n",
    "    #     {\n",
    "    #         \"valid/mse\": total_loss / total_num,\n",
    "    #         \"valid/err\": total_error / total_num,\n",
    "    #         \"valid/dab\": total_dab / total_num,\n",
    "    #         \"valid/sum_mse_dab\": (total_loss + dab_weight * total_dab) / total_num,\n",
    "    #         \"epoch\": epoch,\n",
    "    #     },\n",
    "    # )\n",
    "\n",
    "    if return_raw:\n",
    "        return np.concatenate(predictions, axis=0)\n",
    "\n",
    "    return total_loss / total_num, total_error / total_num\n"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "734a503c",
   "metadata": {},
   "source": [
    "## Step 4: Finetune scGPT with task-specific objectives"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 20,
   "id": "8e48b893",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "random masking at epoch   1, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   1 | 100/975 batches | lr 0.00010 | ms/batch 585.24 | loss  0.94 | cls  0.94 | err  0.29 | \n",
      "riceFM - INFO - | epoch   1 | 200/975 batches | lr 0.00010 | ms/batch 503.10 | loss  0.83 | cls  0.83 | err  0.26 | \n",
      "riceFM - INFO - | epoch   1 | 300/975 batches | lr 0.00010 | ms/batch 502.62 | loss  0.82 | cls  0.82 | err  0.27 | \n",
      "riceFM - INFO - | epoch   1 | 400/975 batches | lr 0.00010 | ms/batch 503.10 | loss  0.79 | cls  0.79 | err  0.25 | \n",
      "riceFM - INFO - | epoch   1 | 500/975 batches | lr 0.00010 | ms/batch 502.99 | loss  0.75 | cls  0.75 | err  0.23 | \n",
      "riceFM - INFO - | epoch   1 | 600/975 batches | lr 0.00010 | ms/batch 503.04 | loss  0.74 | cls  0.74 | err  0.23 | \n",
      "riceFM - INFO - | epoch   1 | 700/975 batches | lr 0.00010 | ms/batch 502.67 | loss  0.70 | cls  0.70 | err  0.22 | \n",
      "riceFM - INFO - | epoch   1 | 800/975 batches | lr 0.00010 | ms/batch 502.52 | loss  0.67 | cls  0.67 | err  0.21 | \n",
      "riceFM - INFO - | epoch   1 | 900/975 batches | lr 0.00010 | ms/batch 502.65 | loss  0.64 | cls  0.64 | err  0.21 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   1 | time: 536.06s | valid loss/mse 0.5411 | err 0.1749\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.5411\n",
      "random masking at epoch   2, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   2 | 100/975 batches | lr 0.00009 | ms/batch 642.10 | loss  0.62 | cls  0.62 | err  0.20 | \n",
      "Loss scaler increasing loss scale to 32768.0\n",
      "riceFM - INFO - | epoch   2 | 200/975 batches | lr 0.00009 | ms/batch 508.25 | loss  0.55 | cls  0.55 | err  0.17 | \n",
      "riceFM - INFO - | epoch   2 | 300/975 batches | lr 0.00009 | ms/batch 506.98 | loss  0.54 | cls  0.54 | err  0.16 | \n",
      "Gradient overflow. Skipping step\n",
      "Loss scaler reducing loss scale to 16384.0\n",
      "riceFM - INFO - | epoch   2 | 400/975 batches | lr 0.00009 | ms/batch 508.82 | loss  0.55 | cls  0.55 | err  0.18 | \n",
      "riceFM - INFO - | epoch   2 | 500/975 batches | lr 0.00009 | ms/batch 508.50 | loss  0.56 | cls  0.56 | err  0.17 | \n",
      "riceFM - INFO - | epoch   2 | 600/975 batches | lr 0.00009 | ms/batch 510.91 | loss  0.55 | cls  0.55 | err  0.17 | \n",
      "riceFM - INFO - | epoch   2 | 700/975 batches | lr 0.00009 | ms/batch 507.04 | loss  0.52 | cls  0.52 | err  0.16 | \n",
      "riceFM - INFO - | epoch   2 | 800/975 batches | lr 0.00009 | ms/batch 508.67 | loss  0.52 | cls  0.52 | err  0.16 | \n",
      "riceFM - INFO - | epoch   2 | 900/975 batches | lr 0.00009 | ms/batch 507.33 | loss  0.50 | cls  0.50 | err  0.16 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   2 | time: 554.28s | valid loss/mse 0.4395 | err 0.1385\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.4395\n",
      "random masking at epoch   3, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   3 | 100/975 batches | lr 0.00008 | ms/batch 653.82 | loss  0.50 | cls  0.50 | err  0.15 | \n",
      "riceFM - INFO - | epoch   3 | 200/975 batches | lr 0.00008 | ms/batch 506.93 | loss  0.44 | cls  0.44 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 300/975 batches | lr 0.00008 | ms/batch 509.03 | loss  0.44 | cls  0.44 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 400/975 batches | lr 0.00008 | ms/batch 507.81 | loss  0.46 | cls  0.46 | err  0.15 | \n",
      "riceFM - INFO - | epoch   3 | 500/975 batches | lr 0.00008 | ms/batch 506.49 | loss  0.46 | cls  0.46 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 600/975 batches | lr 0.00008 | ms/batch 507.11 | loss  0.45 | cls  0.45 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 700/975 batches | lr 0.00008 | ms/batch 507.40 | loss  0.44 | cls  0.44 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 800/975 batches | lr 0.00008 | ms/batch 507.58 | loss  0.43 | cls  0.43 | err  0.14 | \n",
      "riceFM - INFO - | epoch   3 | 900/975 batches | lr 0.00008 | ms/batch 508.31 | loss  0.43 | cls  0.43 | err  0.14 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   3 | time: 553.77s | valid loss/mse 0.4008 | err 0.1284\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.4008\n",
      "random masking at epoch   4, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   4 | 100/975 batches | lr 0.00007 | ms/batch 642.29 | loss  0.43 | cls  0.43 | err  0.13 | \n",
      "riceFM - INFO - | epoch   4 | 200/975 batches | lr 0.00007 | ms/batch 507.27 | loss  0.39 | cls  0.39 | err  0.13 | \n",
      "riceFM - INFO - | epoch   4 | 300/975 batches | lr 0.00007 | ms/batch 507.18 | loss  0.39 | cls  0.39 | err  0.12 | \n",
      "riceFM - INFO - | epoch   4 | 400/975 batches | lr 0.00007 | ms/batch 506.71 | loss  0.39 | cls  0.39 | err  0.12 | \n",
      "Loss scaler increasing loss scale to 32768.0\n",
      "Gradient overflow. Skipping step\n",
      "Loss scaler reducing loss scale to 16384.0\n",
      "riceFM - INFO - | epoch   4 | 500/975 batches | lr 0.00007 | ms/batch 507.09 | loss  0.40 | cls  0.40 | err  0.13 | \n",
      "riceFM - INFO - | epoch   4 | 600/975 batches | lr 0.00007 | ms/batch 506.67 | loss  0.41 | cls  0.41 | err  0.13 | \n",
      "riceFM - INFO - | epoch   4 | 700/975 batches | lr 0.00007 | ms/batch 507.48 | loss  0.39 | cls  0.39 | err  0.13 | \n",
      "riceFM - INFO - | epoch   4 | 800/975 batches | lr 0.00007 | ms/batch 506.79 | loss  0.37 | cls  0.37 | err  0.12 | \n",
      "riceFM - INFO - | epoch   4 | 900/975 batches | lr 0.00007 | ms/batch 507.44 | loss  0.38 | cls  0.38 | err  0.12 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   4 | time: 551.64s | valid loss/mse 0.3806 | err 0.1261\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.3806\n",
      "random masking at epoch   5, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   5 | 100/975 batches | lr 0.00007 | ms/batch 663.90 | loss  0.39 | cls  0.39 | err  0.13 | \n",
      "riceFM - INFO - | epoch   5 | 200/975 batches | lr 0.00007 | ms/batch 508.24 | loss  0.35 | cls  0.35 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 300/975 batches | lr 0.00007 | ms/batch 508.01 | loss  0.34 | cls  0.34 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 400/975 batches | lr 0.00007 | ms/batch 506.74 | loss  0.35 | cls  0.35 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 500/975 batches | lr 0.00007 | ms/batch 507.32 | loss  0.37 | cls  0.37 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 600/975 batches | lr 0.00007 | ms/batch 508.01 | loss  0.38 | cls  0.38 | err  0.12 | \n",
      "riceFM - INFO - | epoch   5 | 700/975 batches | lr 0.00007 | ms/batch 506.77 | loss  0.35 | cls  0.35 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 800/975 batches | lr 0.00007 | ms/batch 506.72 | loss  0.33 | cls  0.33 | err  0.11 | \n",
      "riceFM - INFO - | epoch   5 | 900/975 batches | lr 0.00007 | ms/batch 508.21 | loss  0.34 | cls  0.34 | err  0.11 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   5 | time: 551.90s | valid loss/mse 0.3639 | err 0.1163\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.3639\n",
      "random masking at epoch   6, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   6 | 100/975 batches | lr 0.00006 | ms/batch 656.81 | loss  0.35 | cls  0.35 | err  0.11 | \n",
      "riceFM - INFO - | epoch   6 | 200/975 batches | lr 0.00006 | ms/batch 507.98 | loss  0.32 | cls  0.32 | err  0.11 | \n",
      "riceFM - INFO - | epoch   6 | 300/975 batches | lr 0.00006 | ms/batch 509.02 | loss  0.31 | cls  0.31 | err  0.10 | \n",
      "riceFM - INFO - | epoch   6 | 400/975 batches | lr 0.00006 | ms/batch 507.90 | loss  0.32 | cls  0.32 | err  0.10 | \n",
      "riceFM - INFO - | epoch   6 | 500/975 batches | lr 0.00006 | ms/batch 507.71 | loss  0.34 | cls  0.34 | err  0.11 | \n",
      "Loss scaler increasing loss scale to 32768.0\n",
      "Gradient overflow. Skipping step\n",
      "Loss scaler reducing loss scale to 16384.0\n",
      "riceFM - INFO - | epoch   6 | 600/975 batches | lr 0.00006 | ms/batch 506.70 | loss  0.34 | cls  0.34 | err  0.11 | \n",
      "riceFM - INFO - | epoch   6 | 700/975 batches | lr 0.00006 | ms/batch 506.89 | loss  0.32 | cls  0.32 | err  0.11 | \n",
      "riceFM - INFO - | epoch   6 | 800/975 batches | lr 0.00006 | ms/batch 507.07 | loss  0.30 | cls  0.30 | err  0.10 | \n",
      "riceFM - INFO - | epoch   6 | 900/975 batches | lr 0.00006 | ms/batch 507.19 | loss  0.31 | cls  0.31 | err  0.10 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   6 | time: 553.07s | valid loss/mse 0.3529 | err 0.1123\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.3529\n",
      "random masking at epoch   7, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   7 | 100/975 batches | lr 0.00005 | ms/batch 657.14 | loss  0.33 | cls  0.33 | err  0.11 | \n",
      "riceFM - INFO - | epoch   7 | 200/975 batches | lr 0.00005 | ms/batch 508.90 | loss  0.29 | cls  0.29 | err  0.10 | \n",
      "riceFM - INFO - | epoch   7 | 300/975 batches | lr 0.00005 | ms/batch 507.63 | loss  0.29 | cls  0.29 | err  0.09 | \n",
      "riceFM - INFO - | epoch   7 | 400/975 batches | lr 0.00005 | ms/batch 506.63 | loss  0.29 | cls  0.29 | err  0.09 | \n",
      "riceFM - INFO - | epoch   7 | 500/975 batches | lr 0.00005 | ms/batch 507.35 | loss  0.32 | cls  0.32 | err  0.10 | \n",
      "riceFM - INFO - | epoch   7 | 600/975 batches | lr 0.00005 | ms/batch 507.67 | loss  0.31 | cls  0.31 | err  0.10 | \n",
      "riceFM - INFO - | epoch   7 | 700/975 batches | lr 0.00005 | ms/batch 508.56 | loss  0.30 | cls  0.30 | err  0.10 | \n",
      "riceFM - INFO - | epoch   7 | 800/975 batches | lr 0.00005 | ms/batch 507.11 | loss  0.28 | cls  0.28 | err  0.09 | \n",
      "riceFM - INFO - | epoch   7 | 900/975 batches | lr 0.00005 | ms/batch 507.08 | loss  0.29 | cls  0.29 | err  0.09 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   7 | time: 553.06s | valid loss/mse 0.3439 | err 0.1120\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.3439\n",
      "random masking at epoch   8, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   8 | 100/975 batches | lr 0.00005 | ms/batch 646.84 | loss  0.31 | cls  0.31 | err  0.10 | \n",
      "riceFM - INFO - | epoch   8 | 200/975 batches | lr 0.00005 | ms/batch 507.41 | loss  0.28 | cls  0.28 | err  0.09 | \n",
      "riceFM - INFO - | epoch   8 | 300/975 batches | lr 0.00005 | ms/batch 509.37 | loss  0.27 | cls  0.27 | err  0.09 | \n",
      "riceFM - INFO - | epoch   8 | 400/975 batches | lr 0.00005 | ms/batch 508.66 | loss  0.27 | cls  0.27 | err  0.09 | \n",
      "riceFM - INFO - | epoch   8 | 500/975 batches | lr 0.00005 | ms/batch 507.55 | loss  0.30 | cls  0.30 | err  0.09 | \n",
      "Loss scaler increasing loss scale to 32768.0\n",
      "riceFM - INFO - | epoch   8 | 600/975 batches | lr 0.00005 | ms/batch 507.37 | loss  0.30 | cls  0.30 | err  0.09 | \n",
      "Gradient overflow. Skipping step\n",
      "Loss scaler reducing loss scale to 16384.0\n",
      "riceFM - INFO - | epoch   8 | 700/975 batches | lr 0.00005 | ms/batch 508.21 | loss  0.29 | cls  0.29 | err  0.09 | \n",
      "riceFM - INFO - | epoch   8 | 800/975 batches | lr 0.00005 | ms/batch 506.97 | loss  0.25 | cls  0.25 | err  0.08 | \n",
      "riceFM - INFO - | epoch   8 | 900/975 batches | lr 0.00005 | ms/batch 508.11 | loss  0.26 | cls  0.26 | err  0.09 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   8 | time: 553.15s | valid loss/mse 0.3400 | err 0.1076\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - Best model with score 0.3400\n",
      "random masking at epoch   9, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch   9 | 100/975 batches | lr 0.00004 | ms/batch 654.86 | loss  0.29 | cls  0.29 | err  0.09 | \n",
      "riceFM - INFO - | epoch   9 | 200/975 batches | lr 0.00004 | ms/batch 509.00 | loss  0.25 | cls  0.25 | err  0.08 | \n",
      "riceFM - INFO - | epoch   9 | 300/975 batches | lr 0.00004 | ms/batch 508.39 | loss  0.25 | cls  0.25 | err  0.08 | \n",
      "riceFM - INFO - | epoch   9 | 400/975 batches | lr 0.00004 | ms/batch 508.22 | loss  0.25 | cls  0.25 | err  0.08 | \n",
      "riceFM - INFO - | epoch   9 | 500/975 batches | lr 0.00004 | ms/batch 507.90 | loss  0.27 | cls  0.27 | err  0.08 | \n",
      "riceFM - INFO - | epoch   9 | 600/975 batches | lr 0.00004 | ms/batch 507.54 | loss  0.28 | cls  0.28 | err  0.09 | \n",
      "riceFM - INFO - | epoch   9 | 700/975 batches | lr 0.00004 | ms/batch 508.52 | loss  0.27 | cls  0.27 | err  0.09 | \n",
      "riceFM - INFO - | epoch   9 | 800/975 batches | lr 0.00004 | ms/batch 510.31 | loss  0.24 | cls  0.24 | err  0.08 | \n",
      "riceFM - INFO - | epoch   9 | 900/975 batches | lr 0.00004 | ms/batch 508.12 | loss  0.25 | cls  0.25 | err  0.07 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch   9 | time: 554.98s | valid loss/mse 0.3444 | err 0.1094\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "random masking at epoch  10, ratio of masked values in train:  0.0000\n",
      "riceFM - INFO - | epoch  10 | 100/975 batches | lr 0.00004 | ms/batch 654.30 | loss  0.28 | cls  0.28 | err  0.09 | \n",
      "riceFM - INFO - | epoch  10 | 200/975 batches | lr 0.00004 | ms/batch 507.08 | loss  0.24 | cls  0.24 | err  0.07 | \n",
      "riceFM - INFO - | epoch  10 | 300/975 batches | lr 0.00004 | ms/batch 509.83 | loss  0.24 | cls  0.24 | err  0.08 | \n",
      "riceFM - INFO - | epoch  10 | 400/975 batches | lr 0.00004 | ms/batch 508.33 | loss  0.24 | cls  0.24 | err  0.07 | \n",
      "Gradient overflow. Skipping step\n",
      "Loss scaler reducing loss scale to 8192.0\n",
      "riceFM - INFO - | epoch  10 | 500/975 batches | lr 0.00004 | ms/batch 508.27 | loss  0.27 | cls  0.27 | err  0.08 | \n",
      "riceFM - INFO - | epoch  10 | 600/975 batches | lr 0.00004 | ms/batch 508.07 | loss  0.27 | cls  0.27 | err  0.08 | \n",
      "riceFM - INFO - | epoch  10 | 700/975 batches | lr 0.00004 | ms/batch 507.37 | loss  0.25 | cls  0.25 | err  0.08 | \n",
      "riceFM - INFO - | epoch  10 | 800/975 batches | lr 0.00004 | ms/batch 507.30 | loss  0.22 | cls  0.22 | err  0.07 | \n",
      "riceFM - INFO - | epoch  10 | 900/975 batches | lr 0.00004 | ms/batch 505.91 | loss  0.24 | cls  0.24 | err  0.08 | \n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n",
      "riceFM - INFO - | end of epoch  10 | time: 552.33s | valid loss/mse 0.3455 | err 0.1079\n",
      "riceFM - INFO - -----------------------------------------------------------------------------------------\n"
     ]
    }
   ],
   "source": [
    "best_val_loss = float(\"inf\")\n",
    "best_avg_bio = 0.0\n",
    "best_model = None\n",
    "define_wandb_metrcis()\n",
    "\n",
    "for epoch in range(1, epochs + 1):\n",
    "    epoch_start_time = time.time()\n",
    "    train_data_pt, valid_data_pt = prepare_data(sort_seq_batch=per_seq_batch_sample)\n",
    "    train_loader = prepare_dataloader(\n",
    "        train_data_pt,\n",
    "        batch_size=batch_size,\n",
    "        shuffle=False,\n",
    "        intra_domain_shuffle=True,\n",
    "        drop_last=False,\n",
    "    )\n",
    "    valid_loader = prepare_dataloader(\n",
    "        valid_data_pt,\n",
    "        batch_size=eval_batch_size,\n",
    "        shuffle=False,\n",
    "        intra_domain_shuffle=False,\n",
    "        drop_last=False,\n",
    "    )\n",
    "\n",
    "    if config.do_train:\n",
    "        train(\n",
    "            model,\n",
    "            loader=train_loader,\n",
    "        )\n",
    "    val_loss, val_err = evaluate(\n",
    "        model,\n",
    "        loader=valid_loader,\n",
    "    )\n",
    "    elapsed = time.time() - epoch_start_time\n",
    "    logger.info(\"-\" * 89)\n",
    "    logger.info(\n",
    "        f\"| end of epoch {epoch:3d} | time: {elapsed:5.2f}s | \"\n",
    "        f\"valid loss/mse {val_loss:5.4f} | err {val_err:5.4f}\"\n",
    "    )\n",
    "    logger.info(\"-\" * 89)\n",
    "\n",
    "    if val_loss < best_val_loss:\n",
    "        best_val_loss = val_loss\n",
    "        # best_model = copy.deepcopy(model)\n",
    "        best_model = model\n",
    "\n",
    "        best_model_epoch = epoch\n",
    "        logger.info(f\"Best model with score {best_val_loss:5.4f}\")\n",
    "\n",
    "    scheduler.step()\n",
    "    if DAB_separate_optim:\n",
    "        scheduler_dab.step()\n",
    "    if ADV:\n",
    "        scheduler_D.step()\n",
    "        scheduler_E.step()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 21,
   "id": "4a6ce176",
   "metadata": {},
   "outputs": [],
   "source": [
    "# %% inference\n",
    "def test(model: nn.Module, adata: DataLoader) -> float:\n",
    "\n",
    "    genes = adata.var[\"gene_name\"].tolist()\n",
    "    vocab.set_default_index(vocab[\"<pad>\"])\n",
    "    gene_ids = np.array(vocab(genes), dtype=int)\n",
    "    \n",
    "    all_counts = (\n",
    "        adata.layers[input_layer_key].A\n",
    "        if issparse(adata.layers[input_layer_key])\n",
    "        else adata.layers[input_layer_key]\n",
    "    )\n",
    "\n",
    "    celltypes_labels = adata.obs[\"celltype_id\"].tolist()  # make sure count from 0\n",
    "    celltypes_labels = np.array(celltypes_labels)\n",
    "\n",
    "    batch_ids = adata.obs[\"batch_id\"].tolist()\n",
    "    batch_ids = np.array(batch_ids)\n",
    "\n",
    "    mod_types = adata.obs['mod_type'].tolist()\n",
    "    mod_types = np.array(mod_types)\n",
    "\n",
    "\n",
    "    tokenized_test = tokenize_and_pad_batch(\n",
    "        all_counts,\n",
    "        gene_ids,\n",
    "        max_len=max_seq_len,\n",
    "        vocab=vocab,\n",
    "        pad_token=pad_token,\n",
    "        pad_value=pad_value,\n",
    "        append_cls=True,  # append <cls> token at the beginning\n",
    "        include_zero_gene=include_zero_gene,\n",
    "    )\n",
    "\n",
    "    input_values_test = random_mask_value(\n",
    "        tokenized_test[\"values\"],\n",
    "        mask_ratio=mask_ratio,\n",
    "        mask_value=mask_value,\n",
    "        pad_value=pad_value,\n",
    "    )\n",
    "    test_data_pt = {\n",
    "        \"gene_ids\": tokenized_test[\"genes\"],\n",
    "        \"values\": input_values_test,\n",
    "        \"target_values\": tokenized_test[\"values\"],\n",
    "        \"batch_labels\": torch.from_numpy(batch_ids).long(),\n",
    "        \"mod_labels\": torch.from_numpy(mod_types).long(),\n",
    "        \"celltype_labels\": torch.from_numpy(celltypes_labels).long(),\n",
    "    }\n",
    "    \n",
    "    test_loader = DataLoader(\n",
    "        dataset=SeqDataset(test_data_pt),\n",
    "        batch_size=eval_batch_size,\n",
    "        shuffle=False,\n",
    "        drop_last=False,\n",
    "        num_workers=min(len(os.sched_getaffinity(0)), eval_batch_size // 2),\n",
    "        pin_memory=True,\n",
    "    )\n",
    "\n",
    "    model.eval()\n",
    "    predictions = evaluate(\n",
    "        model,\n",
    "        loader=test_loader,\n",
    "        return_raw=True,\n",
    "    )\n",
    "\n",
    "    # compute accuracy, precision, recall, f1\n",
    "    from sklearn.metrics import accuracy_score, precision_score, recall_score, f1_score\n",
    "\n",
    "    accuracy = accuracy_score(celltypes_labels, predictions)\n",
    "    precision = precision_score(celltypes_labels, predictions, average=\"macro\")\n",
    "    recall = recall_score(celltypes_labels, predictions, average=\"macro\")\n",
    "    macro_f1 = f1_score(celltypes_labels, predictions, average=\"macro\")\n",
    "\n",
    "    logger.info(\n",
    "        f\"Accuracy: {accuracy:.3f}, Precision: {precision:.3f}, Recall: {recall:.3f}, \"\n",
    "        f\"Macro F1: {macro_f1:.3f}\"\n",
    "    )\n",
    "\n",
    "    results = {\n",
    "        \"test/accuracy\": accuracy,\n",
    "        \"test/precision\": precision,\n",
    "        \"test/recall\": recall,\n",
    "        \"test/macro_f1\": macro_f1,\n",
    "    }\n",
    "\n",
    "    return predictions, celltypes_labels, results"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "16236bf2",
   "metadata": {},
   "source": [
    "## Step 5: Inference with fine-tuned scGPT model\n",
    "In the cell-type annotation task, the fine-tuned scGPT predicts cell-type labels for query set as inference. The model performance is evaluated on standard classificaton metrics. Here we visualize the predicted labels over the scGPT cell embeddings, and present the confusion matrix for detailed classification performance on the cell-group level."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "79730e19",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "riceFM - INFO - Accuracy: 0.887, Precision: 0.882, Recall: 0.868, Macro F1: 0.872\n"
     ]
    }
   ],
   "source": [
    "#9m59.9s\n",
    "\n",
    "predictions, labels, results = test(best_model, adata_test)\n",
    "adata_test_raw.obs[\"predictions\"] = [id2type[p] for p in predictions]\n",
    "\n",
    "\n",
    "save_dict = {\n",
    "    \"predictions\": predictions,\n",
    "    \"labels\": labels,\n",
    "    \"results\": results,\n",
    "    \"id_maps\": id2type\n",
    "}\n",
    "with open(save_dir / \"results.pkl\", \"wb\") as f:\n",
    "    pickle.dump(save_dict, f)\n",
    "\n"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 23,
   "id": "2e419279",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "{'test/accuracy': 0.8868648842767451,\n",
       " 'test/precision': 0.8819160087843783,\n",
       " 'test/recall': 0.8680295397357997,\n",
       " 'test/macro_f1': 0.8721278903947809}"
      ]
     },
     "execution_count": 23,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "results"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 24,
   "id": "8403db3d",
   "metadata": {},
   "outputs": [
    {
     "data": {
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dGxwcjNDQUPk8Ly/PaXVVdT///LO8dXynTp3QoUMHk2PLZ/KKFSucXpsrWZvJd999N5o3by6fe1omFxYWIiYmBqWlpejatSuef/55V5ekuevXr+PTTz8FUHZeM3nyZNcWVAXYksflX6+KWazy/GzlypUwGAwAgCFDhiAiIsLovqpVq4ZXX31VPl++fLktJTudyp5Yu69HH30U1atXBwDk5+fj5MmTVm2nJWeey1+5ckX+xFZMTAx69+5tX5EaU9mT9PR0LFmyBEDZ+cpTTz2lpkgXUNkXPeWttVq1aiUf3/i5tfL0krW2stQXPeWtLSz15Wbumre2sNQTPeWttSz1RM9Z68gcm57z1pG+6DVvVc7H6ilrHemLXvPWkZ7oOW/txXlb4zhvax3O2+oTF9sRERF5sN9++00+fvjhh+HtbfrUoEmTJvIfTrm5ufjrr7+cXp87qFWrlnycn5/vwkq0N2/ePGzduhXe3t5YuHAh/P39XV2S5nbu3IkjR44AAB577DEEBQW5uKKqoW7duvJxcnKy2bH/93//hytXrgAAQkNDK2zracpn8iOPPGJ2bJcuXRAYGAgASElJwYkTJ5xam7vw5EyeNm0ajh07hurVq2PBggXw8vJydUmaW7t2LTIzMwEATz/9NHx8fFxckevZksflX2/ZsqXTatKCpSywJW/79u0rH8fHx6OgoEBBhdpTlY8+Pj7yvz+O7qsqsLUvL7/8Mi5duoSwsDB88sknzizNZSz1JC4uDsXFxQCAESNGaFaXq1nqiyfmbfnzz7CwsEqve2LWApb7Yi295a2tffGEvLXUE0/MW0s90XPWOjLHpue81WLu0d3yVmVP9JS1jvRFr3nrSE/0nLf24ryt4zhv69nztnrExXZEREQerPzVI+auxDE2xtOuPDHl8OHD8nGjRo1cV4jGzp49i0mTJgEom5jp2LGjiytyjT///FM+vu+++wAA69evx2OPPYbbb78d/v7+qFu3Lrp27Yo5c+bo+uq+8jp27Ig6deoAAPbu3Yuvv/7a6LjCwkKMGTMGJSUlAIA33njDo/+haUsmV6tWDXfffbfRbT1VUVERUlJS5HNPyuTExETMmTMHAPDee++hSZMmLq7INW7OZCEEli5dip49e6Ju3brw9/dHvXr10LdvXyxYsABFRUUurFYbffv2hZ+fH4CyxYjr1683Oi4nJwexsbHy+YQJEzSpz1nMnZ8JISq8bilvw8PDUb9+fQBASUkJjh49qq5QDak6Z83IyMDly5fl84YNGzpSlsvZ0pfVq1fjhx9+AAB8+eWXqF27tjNLcxlLPbk5a4uKivDll1+iU6dOCA0NRUBAABo0aICBAwdi1apV8k477s5SXwYMGCAfz58/H0lJSUb3k56ejjfffBMA4O3tjTfeeENpnVo5fvw4Zs6cKZ8PGTKkwuuemrWW+mILPeWtrX3xhLy1pieelrfW9ESvWevIHJue81aruUd3yluVPdFT1jraFz3mraM90WvevvDCC2jUqBECAgJQs2ZN3HHHHRgyZAji4uIszhHped7Wkb5Yyx3nbVX1hfO2+lXN1QUQERGR65S/6qhx48YWx5cfc/z4cafU5E4SEhJw7NgxAICfnx969erl4oq0ceMW9Hl5eWjUqBE++OADV5fkMuUnGsLCwjB06FA5UXXDpUuXcOnSJSQkJGD27Nn48ccf0alTJ61L1VRAQADmz5+PYcOGoaioCGPHjsV3332HgQMHIiIiAoWFhThx4gQWL16M9PR0eHl5YdKkSR79k49CiApXOVqbydu2bQPATAbKfpYhOzsbQNnnsX379i6uSBvXr1+XP0Nw77334rXXXnN1SS5TPpNr1aqFbt26ISEhocKY9PR0pKenY8OGDZg1axbWrVuHu+66S+NKtRMeHo45c+bglVdegcFgQP/+/dG9e3f07t0b9evXR25uLo4dO4a4uDhkZWXB19cXs2fPxpNPPunq0u1m6fzswoULcvG7j48PGjRoYHGfjRs3xvnz5wGU5W27du0UV+1cKs9Zyy+gb9++vUN3bXI1W/py+fJljB07FgAwePBgDBw4UJMatWZNT27+oq19+/aVvjw6f/48zp8/j7Vr1+KTTz7BTz/9hNtvv915hTuZNX1p164dJk6ciFmzZiEvLw/3338/HnvsMTz44IOoV68eMjMzceDAASxduhQFBQWoWbMmFi5cWOUvWtq1a5f8Kcfi4mJcunQJ27dvx5o1a+QXTGPHjkW/fv0qbKf3rLW3L7Zwx7xV0Re95a0jPdFr3jrSEz1mraNzbHrNWy3nHt0lb1X2RE9Zq6IvestbFT3RY94CwKZNm+TjwsJC5OXl4cyZM1i9ejWmTp2KxYsXo1u3bpW20/u8rb19sYU7ztuq6AvnbfWNi+2IiIg82NWrV+Xj0NBQi+PLj8nKynJGSW4jPz8fL730knweGxvr1lcA2uKrr75CfHw8AOCbb76p8FMLniY9PV0+njp1KpKTk+Hr64unn34anTt3xi233IIjR47gu+++Q1paGi5evIiePXtix44dFa5u06PHH38cCQkJePnll7F//37s2bMHe/bsqTTuqaeewoQJE3TfD0vy8vLkT1YAzGRbZWRkYOLEifL522+/bfan0fVk6tSpOH78OPz8/PDtt996zHEbUz6TX3zxRSQnJyMwMBAjR45Ehw4d4O3tjf379+Pbb79FVlYWTpw4gYceegh79+616kspdzVu3Dg0bNgQEyZMQEpKCrZs2YItW7ZUGOPl5YVx48YhNjYWzZo1c1GljrPm/Kz8+W9QUBB8fX0t7ted81blOevRo0fx4YcfyufTpk1zuD5XsbUvY8eOxeXLlxEcHIwvvvhCixI1Z01PCgsLK3yGhgwZguTkZISEhGD06NGIiopCSUkJdu7cibi4OFy/fh1JSUno1q0bdu/eXeFng9yFLe+Vjz/+GM2bN8c777wjv4xdu3ZthTF+fn6YNm0ann/+eXlnoapsxowZ+N///mf0tejoaIwfPx7PPPNMpdf0nrX29sVa7pq3Kvqit7y1tyd6zltH3yd6y1pH59j0mrdazT26U96q7ImestbRvugxb1W9V/SUt4GBgejWrRs6dOiARo0awd/fH5cvX8bOnTuxZs0aFBQU4Pz58+jZsydWr16Nxx9/vML2ep23dbQv1nK3eVuVfeG8rc4JIiIi8li+vr4CgAAgTpw4YXH8N998I8f36tVLgwqrJoPBIAYOHCh70bRpU5GTk+PqsjRx+vRpERgYKACIUaNGVXo9Pj5e9qVLly7aF6ix5s2by+MFIG699VaRlJRUaVx2drbo1KmTHBcVFSUMBoMLKtbejh07ROfOnSv0qfwfX19f8fjjj4uUlBRXl6rUmTNn5DE2bNjQ4vgLFy5U6EtxcbHFbf7zn//I8S+88IKCqp3P1r5Y4/r16+L++++X++3UqZNV/atK7O3Ljh07hLe3twAg3n333UqvL1q0SO732WefVVewBuzpib+/f4XPUUREhDh58mSlcRcuXBCRkZFy3KOPPqq4eudw5PNTWloqfv/9d9GqVSuTeVy9enUxYsQIcfHiReccgJNZe362fft2Oeb222+3at9PPfWU3Ob9999XXbrTqDxnvXLlirjzzjvlvoYNG6a4Wu3Y2pdVq1bJsUuWLKn0+vTp0+Xr06dPd2LlzmNtT9LT0ytlR3R0tLh06VKlsUeOHBFhYWFyXGxsrBaHopQ9n6HCwkKxevVq0aBBA5N5W7t2bTFu3DiRm5ur0ZHY75FHHjF6DEFBQWLixIni8OHDRrfTe9ba2xdruHPeOtoXPeatvT3Rc96q+PzoJWtVzLHpMW+1mnt0p7xV2RM9Za2Kvugtb1V/fvSQt7t37zZbW1pamujSpUuFuZHz589XGKPHeVsVfbGGu83bquyLnudtqQwX2xEREXkwLrazz+uvvy77ULNmTXHgwAFXl6QJg8EgHnroIQFAhIeHi6tXr1Ya42mL7Zo1a1bhH9oLFiwwOfbChQsiICBAjt28ebOGlWrv6tWrom/fvgKA8Pf3F1OmTBGHDx8WBQUF4tq1a2LPnj3i5Zdflv/grF27toiPj3d12cpwsZ1xqhfblZSUiMGDB8t9hoeH2zXx42r29KWgoEAu+I2KihJFRUWVxrjzpI09PfHz86vwOdq0aZPJsXv37q0w1przIFez9/Pz77//ig4dOsgvMWfNmiVOnDghCgsLRU5Ojvj777/Fk08+KfcdEREhDh065LwDcRJrz8/0+IWkKarOWa9duyY6duwo99WyZUu3vtDElr5kZGSI0NBQAUD06dPH6Bh3+kLSFGt7kpaWViE7vb29xfHjx03u96effpJjAwICquwXcKbY+hk6fPiwaNq0qcyXefPmibNnz4qioiJx9epV8ccff4jevXvLfbZu3Vr8+++/Gh2N4/Lz80VycrL48ssvRePGjQVQduHM3LlzK431pKy1pS+W6Clvbe2LJ+StLT3xlLy15/Ojl6xVNcemt7zVau7RnfJWZU/0lLWq+qKnvFX9+dFL3lojLy+vwkX1Ny+k9JR525tZ6oslepm3vZk1fdH7vC2V4WI7IiIiDxYcHCxP5g4ePGhx/Ny5c+X4wYMHa1Bh1fPWW2/JHtSoUUP8/fffri5JM5999pk89nXr1hkd42mL7dq1ayePNzAwUFy/ft3s+KFDh8rxkydP1qhK7eXn54vWrVvLifK//vrL5Njvv/9e9iQkJERkZmZqWKnz2LooJicnp8KkjTWTvOW/AJ4wYYKCqp1P5WK70tJSMXz4cLm/sLAwcezYMTWFasyevrzxxhsCgPDx8RF79uwxOsadJ23s6UlISIjc5s4777Q4/t5775Xjv/76awcrdj57epKRkSHq1asngLK7r5r7jHz44Ydy/02bNjU6EVhV2XJ+dvDgQTk2ODjYqv0//vjjcpsvvvhCVdlOpeqcNT8/X3Tv3l3uq3nz5iI9PV1xtdqxtS+DBg0SQNlCq9TUVKNj3OULSVNs6Ulubm6F85UePXqY3bfBYBDh4eFy/IYNG1SX7zS2vleOHTsmatasKTPa3F1CX3rpJbnvhx56SHXpmsjLy6tw9+qbLzrylKy9maW+mKO3vC3Pmr54Qt6WZ6knnpS3N1jzPtFT1qqaY9Nb3mox9+hueauyJ3rKWlV90VPeqnyv6ClvrbV06VKTcy6eMm9rjLm+mKOneVtjLPVF7/O2VIY/CkxEROTBbr31Vvn4ypUrFseXH1N+W08xZcoUfPDBBwCAGjVq4LfffkOnTp1cXJU2Tp06hTfffBMA8MQTT+Cxxx5zcUVVQ+3ateXj1q1bw9/f3+z4e+65Rz4+efKk0+pytXnz5uHQoUMAgGeffRYPPvigybHDhg1D9+7dAQCZmZlYtGiRJjVWNTVq1EC1atXkc2ayeQaDASNHjsSyZcsAAGFhYdi6dSsiIyNdXJk2duzYgU8//RQAMH78eLRr1861BVUR5TO5fN6a4gmZPHPmTKSlpQEAJkyYYPYzMnHiRDRr1gwAcOLECfzyyy+a1OgoW8/PyudldnY2SkpKLP4d7pa3qs5ZCwoK0L9/f2zZsgUAEBkZiYSEBISFhSmtVyu29mXlypVYs2YNAOCjjz5CgwYNNKlTS7b2JDAwEL6+vvK5paz18vJC27Zt5XN3yVp7PkOTJ09Gbm4ugLLsrVu3rsmxs2fPRlBQEAAgISEBe/fuVVS5dgIDAxEXFwcvLy8AwPTp0yGEkK97QtYaY6kvpugtb29mqS+ekLc3s9QTT8nb8qz5/Ogla1XOsekpb7WYe3S3vFXZEz1lrcq+6CVvVX9+9JK3tujWrZt8fO7cOeTn58vnnjxva64vpnjCvK25vnDe1nNUszyEiIiI9CoyMhKnT58GAJw5cwZdu3Y1O/7MmTMVtvUk//nPf+QXLjVr1sSGDRvQsWNHF1elnWXLlsl/MNStWxczZswwOq78e+TcuXMVxk2cONHiYjR3ExkZic2bNwOAnFQwp/w/rHNycpxVlsv9/PPP8nGvXr0sju/du7ec6Ny5c6fT6qrKvLy80KxZMxw9ehRA2WepcePGZrfx1EwuLS1FTEyMnLAJDw/X3YSNJQsWLIDBYICPjw98fX1NZvL+/fvl44MHD8pxAQEBmDBhgia1aikyMlJOdDOTy9iSx97e3ujRowdSUlIAlOXxoEGDnFqfo+w5P6tfvz5q1KiBvLw8lJaWIjU1FXfccYfZbdwpb1Wds+bn51f4IrJFixbYunVrlf0i0hJ7+jJ//nwAZV+sXLlyxWTW/vXXXxUe3xgXFhaG0aNHqyjfKezpiZeXF5o3b47Dhw8D0GfW2tOXwsJCbNy4UT63lLeBgYHo2LEjfvvtNwBleeuOX8A0btwYLVq0wNGjR5GWlobk5GSZkXrPWnPM9cUYveWtKeb6ove8NcVcTzwhb40x1xM9Za3KOTY95a2z5x7dMW9V9kRPWauyL3rJW5U90VPe2qJOnToVnmdlZaF69eoAPHve1lxfjPGUeVtzfeG8refgYjsiIiIPFhUVJf8RlJSUhFGjRpkdn5SUVGFbTzF58mR8/PHHAIBatWphw4YNeOCBB1xclbbKX038+eefW7XN2bNnMXXqVPl83Lhxults16ZNG/k4Ozvb4visrCz52JrJG3d14y5KgHVX7pXvxY2rJj1RVFSUnLRJSkqqcIXczUpKSir8g9xTMrm0tBTPPPMMvv/+ewBAvXr1EB8fL+/G5SluZHJpaSlmzpxp1Tb79++X75mgoCBdTtq0adMGv/76KwBm8g16zmN7z8+8vLzQqlUr7Nq1C0BZ3pr7QjI9PR3nz58HAPj4+OCuu+5SUL1zqDpnvXbtGvr164eEhAQAQMuWLbFlyxazdzOoyuzty42szcvLw7Rp06z6u+Lj4xEfHw8AiI6OrjJfSN7MkfdKmzZt5JeRestae/uSmZmJoqIi+VxveWtOzZo15eOrV6/Kx3rOWmuY6svN9Ja3lpjqi57z1hJz7xU95605pnqip6xVOcemp7x15tyju+atyp7oKWtVv1f0kLcqe6KnvLXFzXerK//rCYDnztta6kt5njRva64vnLf1HPwZWSIiIg/Wt29f+Xjjxo0wGAwmx546dUre6aRmzZpmfxZSTyZMmCC/cAkKCsIff/zhcQvtyLS+ffvC27vslPrQoUMoLCw0O37Pnj3ycfPmzZ1amyuVnxxPTU21OP7cuXPycWhoqFNqcgflM/nGQmhT/vzzT1y7dg0A0LRpUzRt2tSptVUFJSUleOqpp+SETf369fHnn3/qcsKG7NOvXz/5uHzemuIJmazXPHb0/MyWvC3/eteuXXHLLbfYWK02VJ2z5uXloW/fvvKLyNatWyM+Pr7KfxFpCs/lK3O0J7ZkrRAC+/btk8+rctY60pfyWQvoK2/NMRgMOHXqlHx+890d9Ji11rDUlxv0lreWWNsXT2KpJ3rNW3PM9cRTs9Yanpq31vK0vCXbeWLemuOpeXtjYSkANGjQoFI+euq8raW+3OBp87bW9oV0ThAREZHHKi0tFREREQKAACBWrVplcuyYMWPkuGeffVa7Il3otddek8d86623iqSkJFeXVOXFx8fLnnXp0sXV5WiiR48e8pgXLFhgctyFCxdEQECAHLt9+3YNq9RWTEyMPM6uXbuaHVtUVCSaNGkix8+dO1ejKp3rzJkz8pgaNmxo1TZZWVkiMDBQbpeYmGhybJ8+feS46dOnqylaA/b0RQghiouLxeDBg+W2ERER4tSpU84rVGP29sWSRYsWue1/u+3tSdOmTeV2mzZtMjlu7969cpyPj49ITU1VULVz2dOThx56SG4zcuRIs2MzMzNFUFCQHP/zzz8rqFo9FednycnJwtvbWwAQ/v7+Jv//Ly4uFq1bt5Z/36JFixys3jlUnbPm5uaKTp06yX1FR0eLy5cvK65WO1qdy0+fPt1t/pusoifXrl2TWeHt7S2OHz9ucuxPP/0k/75atWqJgoICR8p3GhV9ady4sdzHf//7X7NjU1JShI+Pjxx/4MABe0t3qZUrV8pjCA8PF6WlpRVe11vWWstSX4TQX95aw5q+WOJOeWsNSz3RY95aYqknnpa11s6xeVre2jL36Cl5q3I+Vk9Za21fPClvre2Jp+XttWvXRIsWLeQxjB07ttIYT5i3vZk1fRFC//O2N7O2L5a487wtleFiOyIiIg8XFxcnT+huu+02cezYsUpjfvzxR+Hl5SUnbfR8onzDq6++KvsSHBws9u7d6+qS3IInLrbbvXu3/HzceuutYvfu3ZXGZGdniwcffFD2pnPnzi6oVDubN2+WxwpAvP3228JgMFQaV1hYKIYPHy7HBQYGivT0dBdUrJ69C4XeeecduV3z5s3FhQsXKo2ZPXu2HBMaGiqysrIUVu5c9vSluLhYDBo0SG7XqFEjcebMGafWqTUutqvM3p6sWbPG4uReWlqaiIyMlONGjBihsHLnsacnCxculNt4eXmJ+fPnGx2XnZ1dYfF4/fr1RX5+vsLq1VB5flZ+YXinTp1EdnZ2hdcNBoN45ZVX5JgWLVqI4uJiRw9BOVU9yc3NFR07dpT7atu2rcjMzFRcrXa0PJd3ly8kVfZkzpw5cl9t2rQx+qX10aNHRVhYmBw3bdo0R8p3GlV9mTJlityPn5+fWL9+vdFxaWlpIjo6Wo5t166dI+Ur99VXX4lNmzYZPXcvb+3ataJGjRryOGbMmGF0nF6yVmVf9JS3qt8vlrhD3qruiR7yVmVP9JK11rJljk0veWsNa/uip7y1hIvtjLOlL3rIW2tY2xO95G1cXJz47bffzC7yv3jxoujWrZs8hoCAAHHu3DmjY/Uyb6uyL3qat1X9frHEnedtqUw1EBERkUcbMWIE1q1bh3Xr1uHSpUvo0KEDRo0ahfbt26OwsBC///47fvzxRwghAACzZs3CHXfc4eKqnWvq1KmYO3eufB4bG4vU1FSLt0yPiIhA27ZtnV0eVTH33HMPpk+fjnfeeQdZWVl44IEHMHz4cHTp0gUBAQE4cuQIvv32W6SlpQEAQkJCEBcX59qinax79+4YPnw4li1bBgCYOXMm1q9fj6FDh6JJkyYwGAw4evQoli9fjjNnzsjtZs2ahbCwMFeVbbesrCzMnj27wv+WnZ1d4fUpU6ZU2m7GjBmV/rdJkyZh48aN2LVrF5KTk9GmTRs8//zzaNWqFXJycrB27Vr8/vvvAAAfHx8sWLAAQUFBio9IDVV9GTlyJNasWQMA8PX1xeuvv45//vkH//zzj9m/PzIyEpGRkXZW7zwq3y96obInAwcORExMDOLi4pCamoqoqCiMGjUKHTp0gLe3N/bv34+FCxciKysLANCkSRN8+umnSo9HBVU9iYmJwdKlS/Hnn39CCIEXX3wRS5cuxYABAxAREYHCwkIcOHAAS5cuRUZGBoCybPn666+r3E9gqD4/+/jjj7Ft2zacPHkS27ZtQ1RUFEaPHo0777wTly9fxooVK7Br1y4AQPXq1bFo0SJUq1a1ptFU9qRPnz7Yvn07gLKfDRo3bhz++usvizW0bdsWERERdlTvPDyXr0x1T2JjY7Fx40Zs2rQJ//zzD1q0aIHnnnsO0dHRKCkpwc6dOxEXF4eCggIAwP3334+3335b7UEpoLIvkydPxpo1a3Ds2DEUFRWhf//+ePjhh9GnTx+Eh4fj2rVrSEpKwvLly2WeBwYGYt68eeoPzAGJiYkYO3Ys6tWrhx49eiAqKgp169bFLbfcgtzcXKSkpGDDhg0VzsO6d++OSZMmGd2fHrIWUNsXPeWt6veLHqjuiR7yVmVP9JK1zqCXvFVJT3lLzqeHvFVJL3m7f/9+zJ07F2FhYejVqxeioqIQFhYGf39/XLlyBTt37sTq1auRn58PAPD29sbixYtNZoBe5m1V9kVP87aq3y/kAVy92o+IiIhcr6CgQDz55JMV7kR18x9/f38xZ84cV5eqiS5dupjthak/vPrEM+9sd8OMGTOEn5+f2fdIZGSk0btH6lFxcbGIjY2Vd/0z9ycwMNDk3ZbcQfm7Tdnyx5TMzEzRs2dPs9vWqlVLrFixQsOjtJ2qvjRs2NCu/VTVK7BVv1/McZcrJFX3pKSkRIwbN85i/jzwwANGr0KuClT2JCcnRwwdOtSq7UNDQ8W6des0PlrrOOP87PTp06Jdu3Zmtw8LCxObN2/W7kBtoLIn9uwHqJo/P6b1ubw73P3DGT3Jy8sTQ4YMsbiP/v37V7q7TlWhui9paWmie/fuVu2jUaNGYtu2bdoesBWeffZZq/vg6+srxo8fL65fv252n+6etUKo7Yue8tYZ7xdz3CFvndETd89b1T3RQ9Zay9Y5Nj3krTWs7Yue8tYS3tnOOFv74u55aw1beqKHvC1/F2tLfxo0aCD++OMPi/vUw7ytyr7oad7WGe8Xc9xl3pZM0/dlC0RERGSVgIAArFixAqNHj0ZcXBy2b9+O9PR0+Pn5oX79+ujduzdefPFFNGvWzNWlElVZb7/9NgYNGoSFCxfi999/x/nz55Gfn4+QkBC0a9cOgwcPxtNPP637K4dvqFatGj777DOMGTMGixcvxrZt25CSkoLs7Gx4eXkhODgYLVu2RI8ePRATE4O6deu6uuQqIzg4GH/88QfWrl2L5cuXY/fu3cjIyEBgYCAaNmyIfv364cUXX8Ttt9/u6lKJqiQfHx98/vnnGDFiBBYtWoStW7ciLS0NxcXFuO2223DvvffiySefxIABA+Dl5eXqcp2uZs2aWLlyJcaPH49ly5Zhx44dOH36NHJycuDr64uQkBBER0ejT58+GD58eJW86tpZGjdujMTERCxbtgyrVq3CwYMHcfnyZQQFBaFJkyYYMGAAXnjhBdSuXdvVpRJVOYGBgfjhhx+wZcsWLFmyRP4bUgiB8PBwdOzYETExMejWrZurS9VMeHg4Nm/ejK1bt2LlypVITExEamoq8vLy4O/vjzp16qBt27bo378/nnjiiSp3B1EA+OyzzzBgwAD8/fff2L9/P06dOoXLly+jsLAQgYGBCA0NRatWrdClSxcMGzbMqvNRPWStM/qiB+xLZc7oibvnreqe6CFrnUUPeUvkSu6et6rpIW8nTZqEDh06IDExEfv27cPFixdx5coV5OXloUaNGggLC8M999yDfv36YeDAgfD19bW4Tz3M2zqjL3rAvpCtvIT4/78JR0RERERERERERERERERERERERERGebu6ACIiIiIiIiIiIiIiIiIiIiIiIqKqjovtiIiIiIiIiIiIiIiIiIiIiIiIiCzgYjsiIiIiIiIiIiIiIiIiIiIiIiIiC7jYjoiIiIiIiIiIiIiIiIiIiIiIiMgCLrYjIiIiIiIiIiIiIiIiIiIiIiIisoCL7YiIiIiIiIiIiIiIiIiIiIiIiIgs4GI7IiIiIiIiIiIiIiIiIiIiIiIiIgu42I6IiIiIiIiIiIiIiIiIiIiIiIjIAi62IyIiIiIiIiIiIiIiIiIiIiIiIrKAi+2IiIiIiIiIiIiIiIiIiIiIiIiILOBiOyIiIiIiIiIiIiIiIiIiIiIiIiILuNiOiIiIiIiIiIiIiIiIiIiIiIiIyAIutiMiIiIiIiIiIiIiIiIiIiIiIiKygIvtiIiIiIiIiIiIiIiIiIiIiIiIiCzgYjsiIiIiIiIiIiIiIiIiIiIiIiIiC7jYjoiIiIiIiIiIiIiIiIiIiIiIiMgCLrYjIiIiIiIiIiIiIiIiIiIiIiIisoCL7YiIiIiIiIiIiIiIiIiIiIiIiIgs4GI7IiIiIiIiIiIiIiIiIiIiIiIiIgu42I6IiIiIiIiIiIiIiIiIiIiIiIjIgv8HpPxlBPXA0EQAAAAASUVORK5CYII=",
      "text/plain": [
       "<Figure size 1280x1280 with 4 Axes>"
      ]
     },
     "metadata": {
      "image/png": {
       "height": 1261,
       "width": 1261
      }
     },
     "output_type": "display_data"
    }
   ],
   "source": [
    "y_true = labels\n",
    "y_pred = predictions\n",
    "cell_type_list = np.unique(y_true)\n",
    "# cell_type_list=[\n",
    "#        'Root stele', 'Mesophyll precursor/Root endodermis', 'Mesophyll/Cortex',\n",
    "#        'Mestome sheath', 'Parenchyma', 'Pericycle', 'Phloem',\n",
    "#        'Procambium', 'Unknow', 'Vascular tissue', 'Xylem',\n",
    "#        'Epidermis', 'Fiber cell', 'Initial cell']\n",
    "# cell_type_list = np.array(cell_type_list)\n",
    "matrix = confusion_matrix(y_true, y_pred, labels=cell_type_list)\n",
    "matrix = matrix.astype(\"float\") / matrix.sum(axis=1)[:, np.newaxis]\n",
    "\n",
    "df = pd.DataFrame(matrix, index=cell_type_list[:matrix.shape[0]], columns=cell_type_list[:matrix.shape[1]])\n",
    "\n",
    "ax = sns.clustermap(df,\n",
    "                    cmap='Purples',\n",
    "                    annot=True ,fmt=\".2f\", \n",
    "                    annot_kws={'size': 6}, \n",
    "                    vmin=0, \n",
    "                    vmax=1,\n",
    "                    row_cluster=False, \n",
    "                    col_cluster=False, \n",
    "                    figsize=(16, 16))\n",
    "plt.savefig(str(save_dir / \"confusion_matrix.png\"), dpi=300, bbox_inches='tight')"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 25,
   "id": "62ebbbb9",
   "metadata": {},
   "outputs": [],
   "source": [
    "# save the model into the save_dir\n",
    "torch.save(best_model.state_dict(), save_dir / \"model.pt\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 26,
   "id": "66e4af22",
   "metadata": {},
   "outputs": [],
   "source": [
    "adata_test_raw.obsm.clear()\n",
    "adata_test_raw.write_h5ad(save_dir / \"GSE232863_test_raw_predictions.h5ad\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 28,
   "id": "a761f013",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "AAACAGCCAGGCTACT-1       Bud--Bud_primordium\n",
       "AAACAGCCATAGACTT-1        Bud--Root_meristem\n",
       "AAACAGCCATGTCAAT-1      Bud--Parenchyma_cell\n",
       "AAACATGCAATGCCCG-1          Bud--Bud-unknown\n",
       "AAACATGCACTATGGC-1      Bud--Parenchyma_cell\n",
       "                               ...          \n",
       "TTTGTGTTCCTAACGG-14    ST--Vascular_cylinder\n",
       "TTTGTGTTCTGTGCAG-14      ST--Parenchyma_cell\n",
       "TTTGTTGGTGCTTTAC-14    ST--Vascular_cylinder\n",
       "TTTGTTGGTTACCGGG-14      ST--Parenchyma_cell\n",
       "TTTGTTGGTTATCGAG-14      ST--Parenchyma_cell\n",
       "Name: predictions, Length: 80753, dtype: category\n",
       "Categories (56, object): ['Bud--Bud-unknown', 'Bud--Bud_axis', 'Bud--Bud_primordium', 'Bud--Epidermis', ..., 'leaf--Guard_cell', 'leaf--Mesophyll', 'leaf--Parenchyma_cell', 'leaf--Vascular_cylinder']"
      ]
     },
     "execution_count": 28,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "adata_test_raw.obs['predictions']"
   ]
  }
 ],
 "metadata": {
  "kernelspec": {
   "display_name": "scgpt_new",
   "language": "python",
   "name": "python3"
  },
  "language_info": {
   "codemirror_mode": {
    "name": "ipython",
    "version": 3
   },
   "file_extension": ".py",
   "mimetype": "text/x-python",
   "name": "python",
   "nbconvert_exporter": "python",
   "pygments_lexer": "ipython3",
   "version": "3.10.18"
  }
 },
 "nbformat": 4,
 "nbformat_minor": 5
}
